Soil-derived mycobacterium promotes immunoregulation and stress resilience

Abstract

The present invention describes a novel isolated Mycobacterium species designated MTC 0012 (PTA-127651) and its anti-inflammatory, immunoregulatory, and stress resilience effects in subjects in need thereof. The present invention describes the use of MTC 0012 for the treatment and / or prophylactic prevention of trauma- and stressor-related disorders, such as PTSD.

Description

[0001]SOIL-DERIVED MYCOBACTERIUM PROMOTES IMMUNOREGULATION AND STRESS RESILIENCE STATEMENT OF GOVERNMENT INTEREST This invention was made with government support under grant numbers R41 AT011390 awarded by the National Institutes of Health. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS This International PCT application claims the benefit of and priority to U.S. Provisional Application No 63 / 538,179, filed September 13, 2023, the specification, claims and drawings of which are incorporated herein by reference in their entirety. DEPOSIT INFORMATION The bacterial strain MTC 0012 has been deposited in an international depository under conditions that assure that access to the culture will be available during the pendency of this patent application and any patent(s) issuing therefrom to one determined by the Commissioner of Patents and Trademarks to be entitled thereto under 37 C.F.R. 1.14 and 35 U.S.C. 122. This strain has been deposited in the American Type Culture Collection (ATCC), at 10801 University Boulevard, Manassas, VA 20110-2209 United States of America, and has been assigned the Patent Deposit Number PTA-127651. TECHNICAL FIELD This invention relates generally to the field of neuroinflammation, immunoregulation, and stress resilience, and in particular to a novel isolated Mycobacterium (MTC 0012, also referred to as PTA-127651) for use in the treatment and / or prophylactic prevention symptoms associated with posttraumatic stress disorder (PTSD). BACKGROUND Current treatments for mental health disorders do not adequately address the needs of patients and the general public for their mental health needs. Current pharmacological treatment response rates for major mental health disorders such as posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and general anxiety disorder (GAD) are ~50%. Additionally, the gold standard medications for these disorders have many unfavorable side effects. There is a desperate need for more effective medications with fewer unfavorable side effects. A wide range of evidence suggests that exaggerated or inappropriate peripheral inflammation is a causal mediator of stress-related psychiatric disorders. A number of factors predispose individuals towards peripheral proinflammatory immune responses and, of these, alterations in the microbiome have received a great deal of recent attention. Humans (and rodents) harbor and interact with a broad diversity of microorganisms, which constitute the microbiome. Interestingly, the interactions of these microorganisms with cells and organs of the immune system have shaped how these cells and organs respond, and normally prime immunoregulatory circuits as well as suppress pathological inflammation. However, it is thought that the microbiome of humans (and laboratory rodents) has shifted radically as a result of modern sanitary conditions (the hygiene hypothesis”), with entire classes of microorganisms now either absent or much reduced (the “old friends” hypothesis). It has been argued that these changes in the microbiome, and microbial exposures more generally, alter the manner in which the peripheral immune system responds to challenge, resulting in a shift towards imbalanced immunoregulation, an imbalance indicated by deficits in development of regulatory T cells (Treg). Recent preclinical studies have demonstrated that the microbiome plays a critical role in neuronal function and fear extinction learning, while recent clinical studies demonstrate a role for lipopolysaccharide (LPS)-induced inflammation in fear extinction deficits. This thinking has led to efforts to ameliorate psychiatric disorders by restoring some of the lost “old friends” through microbial-based therapeutics, thereby shifting immunoregulation towards a more balanced response. A growing number of reports demonstrate that administration of microorganisms, such as Lactobacillus spp., blunts the behavioral changes produced by both acute and chronic stressors. Interestingly, heat-killed bacteria have the same peripheral anti- inflammatory impact as do live bacteria. See Kummola L, Gonzalez-Rodriguez MI, Marnila P et al. Comparison of the effect of autoclaved and non-autoclaved live soil exposure on the mouse immune system : Effect of soil exposure on immune system. BMC Immunol 2023;24:29. Of note, Reber et al. reported that the administration of heat-killed Mycobacterium vaccae NCTC 11659 substantially reduces the colitogenic and anxiogenic effects of chronic social stress in mice. Heat- killed M. vaccae NCTC 11659 was used because this preparation produces very long-lasting (up to 12 weeks) peripheral anti-inflammatory and immunoregulatory effects. Considerable effort has been devoted to determining the precise nature of the peripheral immune changes produced by the administration of microbial agents, both basally and in response to stressors. For example, heat-killed M. vaccae NCTC 11659, induces Treg and peripheral secretion of anti-inflammatory cytokines, including interleukin (IL)-10 and transforming growth factor beta (TGFβ). However, any amelioration of the behavioral effects of stressors ultimately has to be mediated by changes in the brain. Applicants have found that immunization with a heat- killed preparation of the soil-derived Mycobacterium, M. vaccae NCTC 11659, can prevent development of a PTSD-like syndrome in a murine model of PTSD. See Table 1 below that summarizes beneficial effects of M. vaccae NCTC 11659 on individual PTSD symptoms. However, more effective microbial strains that can be used in therapeutic setting to are needed to adequately address immunoregulation and stress resilience in human patients. SUMMARY OF THE INVENTION The present invention describes a novel isolated Mycobacterium species designated MTC 0012, also referred to herein as PTA-127651, and its anti-inflammatory, immunoregulatory, and stress resilience effects in a subject in need thereof. The present invention describes the use of MTC 0012 for the treatment and / or prophylactic prevention of one or more disease or conditions. In one aspect, the isolated Mycobacterium MTC 0012 can be used to treat inflammation, and preferably neuroinflammation, as well as promote stress resilience in a subject in need thereof. In another aspect, the isolated Mycobacterium MTC 0012 can be used to treat one or more symptoms of trauma and stressor-related disorders such as PTSD, as well as other anxiety and / or mood disorders such as GAD or MDD as generally defined by the DMS-5. In a further aspect, the isolated Mycobacterium MTC 0012can include a pharmaceutically acceptable carrier forming a pharmaceutical compositions for the treatment of one or more symptoms of a disease or condition, and preferably PTSD, GAD or MDD. In a preferred aspect, the pharmaceutical compositions of the invention can be configured for oral administration to a subject in need thereof. Additional embodiments of the invention may become evident in light of the figures and disclosure provided below. BRIEF DESCRIPTION OF FIGURES Figure 1. Bar plot of 15 novel mycobacterial strains isolated and ranked by Applicants’ algorithm developed to take in multiple variables from Applicants’ in vitro screening and produce an immunoregulatory score to rank strains in an unbiased manner (higher scores represent higher immunoregulatory potential). MTC 0012 (black bar) is Applicants’ lead strain and was used for in vivo studies (data below). MTC 0003 (gray bar) was used as a negative control for in vivo studies. (Algorithm variables can include IL-10, IL-6, IL-12a, IL-4, IL-12b, and ratios of the same). Figure 2. Inescapable tail shock stress (IS) in adult male rats increases anxiety-like defensive behavioral responses (i.e., avoidance behaviors) in the IS / juvenile social exploration (JSE) paradigm. Immunization with immunoregulatory A) MTC 0012, but NOT proinflammatory B) MTC 0003, prevented the IS-induced exaggeration of anxiety-like defensive behavioral responses. The magnitude of the effects of MTC 0012 are comparable to those in Applicants’ published studies using M. vaccae strains. *p < 0.05, ***, p < 0.001, Tukey’s HSD post hoc pairwise comparisons; ****p < 0.0001, main effect of IS. Figure 3. Inescapable tail shock stress (IS) in adult male rats increases hippocampal Il6 mRNA expression and systemic C-reactive protein (CRP). Immunization with MTC 0012 prevents IS-induced increase in A) hippocampal Il6 mRNA expression and B) plasma CRP concentrations. *p < 0.05, **p < 0.01, Tukey’s HSD post hoc pairwise comparisons. DESCRIPTION OF THE INVENTION The present invention is directed to a novel isolated Mycobacterium strain (MTC 0012) which has demonstrated improved anti-inflammatory / immunoregulatory effects in vitro (Figure 1), stress resilience effects in behavioral models (Figure 2), and immunoregulatory effects in vivo (Figure 3). In a preferred embodiment, MTC 0012 is heat killed prior to administration to a subject. As described herein, Applicants isolated 15 novel soil-derived strains of Mycobacterium which were subsequently screened for anti-inflammatory and immunoregulatory potential using GM- CSF-derived murine bone marrow-derived dendritic cells (BMDCs). Applicants developed an algorithm to rank each strain on their anti-inflammatory / immunoregulatory potential using ten differentially weighted input variables. In certain embodiment, the input variables can include Il10, Il6, Il4, Il12a (encoding the IL-12p35 subunit), and Il12b (encoding the IL-12p40 subunit) mRNA both individually and as ratios assessed following immune challenge with lipopolysaccharide (LPS) (more heavily weighted) or no LPS (less heavily weighted). Mycobacterium MTC 0012 achieved the highest rank using this algorithm (MTC 0009 ranked lowest) of anti-inflammatory / immunoregulatory bioactivity in vitro (Figure 1). Applicants used this algorithm to remove bias from picking the lead strain for in vivo testing. Indeed, Mycobacterium MTC 0012 shows anti- inflammatory / immunoregulatory effects in vitro and MTC 0012 has stress resilience behavioral effects in rats when given by subcutaneous (s.c.) injection in vivo (Figure 2A). MTC 0003 (a novel proinflammatory strain) did NOT have stress resilient effects in rats when given by subcutaneous (s.c.) injection in vivo (Figure 2B). Additionally, in the behavioral experiments, MTC 0012: 1) prevented stress-induced increases in hippocampal Il6 mRNA expression (Figure 3A), and 2) prevented stress-induced increases in plasma C-reactive protein (CRP) (Figure 3B). As such, MTC 0012 is effective in: 1) promoting an immunoregulatory phenotype in vivo; 2) preventing stress- induced exaggeration of anxiety-like defensive behavioral responses; 3) and promoting anti- neuroinflammatory and systemic anti-inflammatory effects in vivo. The present invention includes the use of Mycobacterium strain MTC 0012 to promote anti-inflammatory and immunoregulatory effects in a subject in need thereof. The present invention further includes the use of Mycobacterium strain MTC 0012 to prevent and / or treat neuroinflammation in subjects experiencing anxiety, stress, or PTSD. In a preferred embodiment, present invention further includes the use of Mycobacterium strain MTC 0012 to treat and / or prevent one or more symptoms associated with PTSD in a subject in need thereof. In another preferred embodiment, present invention further includes the use of Mycobacterium strain MTC 0012 to treat and / or prevent one or more symptoms associated with major depressive disorder (MDD), and / or general anxiety disorder (GAD) in a subject in need thereof. The present invention further includes a pharmaceutical composition containing isolated Mycobacterium strain MTC 0012, or its constituent parts, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition promotes anti-inflammatory and immunoregulatory effects in a subject in need thereof. The present invention further includes a pharmaceutical composition containing isolated Mycobacterium strain MTC 0012, or its constituent parts, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition treats and / or prevents one or more symptoms associated with PTSD in a subject in need thereof. The present invention further includes a pharmaceutical composition containing isolated Mycobacterium strain MTC 0012, or its constituent parts, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition treats and / or prevents one or more symptoms associated with major depressive disorder (MDD), and / or general anxiety disorder (GAD) in a subject in need thereof. This disclosure also provides methods of treating or reducing the incidence of GAD in a patient by administering a therapeutically effective amount of an isolated Mycobacterium strain MTC 0012, or its constituent parts, to the subject. As used herein, a “therapeutically effective amount” for treating “a disease or condition” means a quantity of MTC 0012 that is needed or desirous to treat the disease or condition, such as by ameliorating one or more symptoms of the disease or condition in a subject in need thereof. This disclosure also provides methods of treating or reducing the incidence of neuroinflammation by administering a therapeutically effective amount of an isolated Mycobacterium strain MTC 0012, or its constituent parts, to the subject. This disclosure also provides methods of treating or reducing the incidence of GAD in a patient by administering a therapeutically effective amount of an isolated Mycobacterium strain MTC 0012, or its constituent parts, to the subject. This disclosure also provides methods of treating or reducing the incidence of MDD in a patient by administering a therapeutically effective amount of an isolated Mycobacterium strain MTC 0012, or its constituent parts, to the subject. In these embodiments, the Mycobacterium MTC 0012 may be a whole cell. Alternatively, or additionally, Mycobacterium MTC 0012 may comprise a non-pathogenic heat-killed bacterium. In these methods, the Mycobacterium MTC 0012 may comprise the constituent parts of the Mycobacterium MTC 0012, which may include organelles or biomolecules isolated from (e.g, extracted from) Mycobacterium MTC 0012. In these methods, the Mycobacterium MTC 0012 may be in the form of a vaccine composition optionally comprising an adjuvant. In these methods, the Mycobacterium MTC 0012 may be administered in two or more repeated doses. Alternatively, or additionally, in these methods, the Mycobacterium may be administered in a unit dose comprising an effective amount of non-pathogenic heat-killed Mycobacterium MTC 0012 from 107to 109cells. In these methods, the Mycobacterium MTC 0012 may be administered as a vaccination, which may be administered weekly, for example three separate vaccinations administered weekly to the subject. In these methods, the Mycobacterium MTC 0012 may be formulated for administration via the parenteral, oral, sublingual, nasal or pulmonary route. In these methods, the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitoneal, intravenous, or intravesicular injection. In particular, the Mycobacterium MTC 0012 may be formulated for administration via the oral route. In these methods, the administration may prevent at least one sign or symptom of stress, anxiety, or in a preferred embodiment a trauma or stressor related-disorder such as PTSD wherein the sign or symptom is selected from disorganized or agitated behavior, problems with pain perception and pain tolerance, headache, difficult falling or staying asleep, or frightening dreams. As used herein, the terms “patient” and / or “subject” can be used interchangeably. For the avoidance of doubt, the present invention is intended preferably for use in humans; however, non- human vertebrate animals (Veterinary use) can also be subject to the treatment or preventative therapy. For example, horses and dogs are often used in military or police operations as well as in other instances, such as on racetracks, where they may become exposed to traumatic conditions. The therapy of the invention can therefore be of use to restore performance in such animals. As used herein, the term “preventing” refers to any manner in which at least one sign, symptom, or symptom cluster of a disease or disorder is beneficially altered so as to prevent or delay the onset, retard the progression, prevent relapse, or ameliorate the symptoms or associated symptoms of the disease or disorder. For example, in PTSD, preventing the disorder can, in certain embodiments, prevent the occurrence of at least one of a sign, symptom, and symptom cluster of PTSD. For example, with respect to “inflammation: and in particular “neuroinflammation,” the invention can include preventing the neuroinflammation and can, in certain embodiments, prevent the occurrence of at least one of a sign, symptom, and symptom cluster of neuroinflammation. As used herein the phrase “diagnosed with posttraumatic stress disorder (PTSD)” refers to having a sign, symptom, or symptom cluster indicative of PTSD, a psychiatric disorder triggered by a traumatic event. Non-limiting examples of such traumatic events include military combat, terrorist incidents, physical assault, sexual assault, motor vehicle accidents, and natural disasters. The Diagnostic and Statistical Manual of Mental Disorders-5 revised (DSM-5), a handbook for mental health professionals that lists categories of mental disorders and the criteria, classifies PTSD as an anxiety disorder. According to the DSM-5, a PTSD diagnosis can be made if: (1) the patient experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others and the response involved intense fear, helplessness, or horror; (2) as a consequence of the traumatic event, the patient experiences at least one re-experiencing / intrusion symptom, three avoidance / numbing symptoms, and two hyper-arousal symptoms, and the duration of the symptoms is for more than one month; and (3) the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. In certain embodiments, if the patient's disorder fulfils DSM-5 criteria, the patient is diagnosed with PTSD. In certain embodiments, if the patient has at least one sign, symptom, or symptom cluster of PTSD, the patient is diagnosed with the disorder. In certain embodiments, a scale is used to measure a sign, symptom, or symptom cluster of PTSD-, and the disorder is diagnosed on the basis of the measurement using that scale. In certain embodiments, a “score” on a scale is used to diagnose or assess a sign, symptom, or symptom cluster of PTSD. In certain embodiments, a “score” can measure at least one of the frequency, intensity, or severity of a sign, symptom, or symptom cluster of PTSD. As used herein, the term “symptom” and “symptoms” refer to subjective indications that characterize a disorder, which can include neuroinflammation and or mis-regulation of the immune system. In one embodiment, symptoms of PTSD may refer to, for example, but not limited to recurrent and intrusive trauma recollections, recurrent and distressing dreams of the traumatic event, acting or feeling as if the traumatic event were recurring, distress when exposed to trauma reminders, physiological reactivity when exposed to trauma reminders, efforts to avoid thoughts or feelings associated with the trauma, efforts to avoid activities or situations, inability to recall trauma or trauma aspects, markedly diminished interest in significant activities, feelings of detachment or estrangement from others, restricted range of affect, sense of a foreshortened future, social anxiety, anxiety with unfamiliar surroundings, difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hyper-vigilance, problems with pain perception, pain tolerance, and exaggerated startle response. In certain embodiments, potentially threatening stimuli can cause hyper-arousal or anxiety. In certain embodiments, the physiological reactivity manifests in at least one of abnormal respiration, abnormal cardiac rate of rhythm, abnormal blood pressure, abnormal function of a special sense, and abnormal function of sensory organ. In certain embodiments, restricted range of affect characterized by diminished or restricted range or intensity of feelings or display of feelings can occur and sense of a foreshortened future can manifest in thinking that one will not have a career, marriage, children, or a normal life span. In certain embodiments, children and adolescents may have symptoms of PTSD such as, for example and without limitation, disorganized or agitated behavior, repetitive play that expresses aspects of the trauma, frightening dreams which lack recognizable content, and trauma-specific re-enactment. In certain embodiments, a symptom can be stress associated with memory recall. As used herein, the term “symptom cluster” refers to a set of signs, symptoms, or a set of signs and symptoms, which are grouped together because of their relationship to each other or their simultaneous occurrence. As used herein, the term “re-experiencing / intrusion” refers to at least one of recurrent and intrusive trauma recollections, recurrent and distressing dreams of the traumatic event, acting or feeling as if the traumatic event were recurring, distress when exposed to trauma reminders, and physiological reactivity when exposed to trauma reminders. In certain embodiments, the physiological reactivity manifests in at least one of abnormal respiration, abnormal cardiac rate of rhythm, abnormal blood pressure, abnormal function of a special sense, and abnormal function of sensory organ. As used herein, the term “avoidance / numbing” refers to at least one of efforts to avoid thoughts or feelings associated with the trauma, efforts to avoid activities or situations, inability to recall trauma or trauma aspects, markedly diminished interest in significant activities, feelings of detachment or estrangement from others, restricted range of affect, and sense of a foreshortened future. Restricted range of affect characterized by diminished or restricted range or intensity of feelings or display of feelings can occur. A sense of a foreshortened future can manifest in thinking that one will not have a career, marriage, children, or a normal life span. Avoidance / numbing can also manifest in social anxiety and anxiety with unfamiliar surroundings. As used herein, the term “hyper-arousal” refers to at least one of difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hyper-vigilance, and exaggerated startle response. Potentially threatening stimuli can cause hyper-arousal or anxiety. As used herein, the term “significantly” refers to a set of observations or occurrences that are too closely correlated to be attributed to chance. For example, in certain embodiments, “significantly changes”, “significantly reduces”, and “significantly increases” refers to alterations or effects that are not likely to be attributed to chance. In certain embodiments, statistical methods can be used to determine whether an observation can be referred to as “significantly” changed, reduced, increased, or altered. As used herein, the phrase “improving resilience” refers to increasing the ability of a patient to experience a traumatic event without suffering PTSD or with less post-event symptomatology or less disruption of normal activities of daily living. In certain embodiments, improving resilience can, in certain embodiments, reduce at least one of the signs, symptoms, or symptom clusters of PTSD. In certain embodiments the re-experiencing / intrusion comprises at least one of recurrent and intrusive trauma recollections, recurrent and distressing dreams of the traumatic event, acting or feeling as if the traumatic event were recurring, distress when exposed to trauma reminders, and physiological reactivity when exposed to trauma reminders. In certain embodiments the physiological reactivity comprises at least one of abnormal respiration, abnormal cardiac rate of rhythm, abnormal blood pressure, abnormal function of at least one special sense, and abnormal function of at least one sensory organ. In certain embodiments at least one special sense is selected from sight, hearing, touch, smell, taste, and sense. In certain embodiments at least one sensory organ is selected from eye, ear, skin, nose, tongue, and pharynx. In certain embodiments the avoidance / numbing comprises at least one of efforts to avoid thoughts or feelings associated with the trauma, efforts to avoid activities or situations, inability to recall trauma or trauma aspects, markedly diminished interest in significant activities, feelings of detachment or estrangement from others, restricted range of affect, sense of a foreshortened future, social anxiety, and anxiety associated with unfamiliar surroundings. In certain embodiments the hyper-arousal comprises at least one of difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hyper-vigilance, exaggerated startle response, and anxiety from potentially threatening stimuli. In certain embodiments the isolated Mycobacterium MTC 0012 does not reduce the physical ability of the patient to respond appropriately and promptly to the potentially threatening stimuli. In certain embodiments the isolated Mycobacterium MTC 0012 reduces the difficulty of staying asleep by reducing stress associated with memory recall and dreaming. In certain embodiments the patient is a child or an adolescent. In some embodiments, the patient is an adult. In certain embodiments the isolated Mycobacterium MTC 0012 prevents at least one sign or symptom of the PTSD in the patient, wherein the sign or symptom is selected from disorganized or agitated behavior, problems with pain perception and pain tolerance, headache, difficult falling or staying asleep, repetitive play that expresses aspects of the trauma, frightening dreams which lack recognizable content, and trauma-specific re-enactment. In certain embodiments the isolated Mycobacterium MTC 0012 reduces the incidence of at least one disorder comorbid with PTSD selected from drug abuse, alcohol abuse, and depression in the patient. In certain embodiments the isolated Mycobacterium MTC 0012 is administered to the patient before or immediately after a traumatic event. In certain embodiments the isolated Mycobacterium MTC 0012 reduces the incidence of at least one sign, symptom, or symptom cluster of PTSD as diagnosed or assessed with at least one of Clinician-Administered PTSD Scale (CAPS-5), Clinician-Administered PTSD Scale Part 2 (CAPS-2), Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA), Impact of Event Scale (IES), Impact of Event Scale-Revised (IES-R), Clinical Global Impression Scale (CGI), Clinical Global Impression Severity of Illness (CGI-S), Clinical Global Impression Improvement (CGI-I), Duke Global Rating for PTSD scale (DGRP), Duke Global Rating for PTSD scale Improvement (DGRP-I), Hamilton Anxiety Scale (HAM-A), Structured Interview for PTSD (SI-PTSD), PTSD Interview (PTSD-I), PTSD Symptom Scale (PSS-I), Mini International Neuropsychiatric Interview (MINI), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Hamilton Depression Scale (HAM-D), Revised Hamilton Rating Scale for Depression (RHRSD), Major Depressive Inventory (MDI), Geriatric Depression Scale (GDS-30), and Children's Depression Index (CDI). In certain embodiments the isolated Mycobacterium MTC 0012 significantly changes or reduces a score on at least one of CAPS, CAPS-2, CAPS-CA, IES, IES-R, CGI, CGI-S, CGI-I, DGRP, DGRP-I, HAM-A, SI-PTSD, PTSD-I, PSS-I, MADRS, BDI, HAM-D, RHRSD, MDI, GDS-30, and CDI. In certain embodiments an overall score of at most 65 on at least one of the CAPS-5 and the CAP-2 is indicative of prevention of PTSD. In certain embodiments an overall score of at most 18 on HAM-A is indicative of prevention of anxiety disorder. In certain embodiments a score of at most 3 on at least one of the CGI-I and the DGRP-I is indicative of prevention of PTSD. In a further embodiment, the isolated Mycobacterium MTC 0012 prevents and / or reduces low-grade inflammation concomitant with PTSD. Such low-grade inflammation may be indicated by elevated serum levels of C-reactive protein, such as greater than 1 mg / liter. In a yet further embodiment, the isolated Mycobacterium MTC 0012 prevents and / or reduces the incidence of histological damage associated with PTSD and / or concomitant inflammation, such as the colon or other parts of the gastrointestinal tract. In one embodiment, administration, as defined herein, includes the administration of the isolated Mycobacterium MTC 0012 in multiple aliquots and / or doses and / or on separate occasions. Preferably the isolated Mycobacterium MTC 0012 is administered before, and continued to be administered to the patient after a traumatic event occurs. More preferably, the isolated Mycobacterium MTC 0012 is continued to be administered to the patient after a traumatic event occurs. In one aspect of the present invention the isolated Mycobacterium MTC 0012 comprises heat-killed Mycobacterium MTC 0012. Preferably, the heat-killed Mycobacterium MTC 0012 is non-pathogenic. In a preferred embodiment, the amount of isolated Mycobacterium administered to the patient is sufficient to elicit a protective immune response in the patient such that it prevents at least one sign or symptom of neuroinflammation, stress resilience, and / or the PTSD in the patient. In certain embodiments of the invention, it is preferable that a particular dosage of isolated Mycobacterium MTC 0012 be administered to a subject. Thus, in certain embodiments of the invention, there is provided a containment means comprising the effective amount of heat- killed Mycobacterium MTC 0012 for use in the present invention, which typically may be from 103to 1011organisms, preferably from 104to 1010organisms, more preferably from 106to 1010organisms, and even more preferably from 106to 109organisms per unit dose. The effective amount of heat-killed Mycobacterium MTC 0012 for use in the present invention may be from 103to 1011organisms, preferably from 104to 1010organisms, more preferably from 106to 1010organisms, and even more preferably from 106to 109organisms. Most preferably the amount of heat-killed Mycobacterium MTC 0012 for use in the present invention is from 107to 109cells or organisms. Typically, the composition according to the present invention may be administered at a dose of from 108to 109cells for human and animal use. Alternatively, the dose is from 0.01 mg to 1 mg or 0.1 mg to 1 mg organisms presented as either a suspension or dry preparation. In one embodiment there is provided an isolated Mycobacterium MTC 0012, for administration to a patient to reduce the elevation of the patient's levels of inflammatory cytokines such as IL-6 following exposure to a traumatic event. In another embodiment, there is provided an isolated Mycobacterium MTC 0012, for administration to a patient to prevent the patient's levels of inflammatory cytokines such as IL-6 or IL-1β or IL-8 or TNF-alpha or MCP-1 from becoming elevated following exposure to a traumatic event. The Mycobacterium MTC 0012 reduces the elevation of the patient's levels of IL- 6 or IL-1β or IL-8, TNF or MCP-1, following exposure to a traumatic event. In a further embodiment, the isolated Mycobacterium MTC 0012 produces an immunomodulatory effect, wherein the ratio of inflammatory to regulatory cytokines present in the plasma of a subject, is maintained at below about 1, respectively. Such inflammatory cytokines include the likes of IL-6, TNF and interferon-gamma, whereas regulatory cytokines include the likes of IL-10 and TGF-beta. The term “combination” as used throughout the specification, is meant to encompass the administration of the therapeutic agents in the same or separate pharmaceutical formulations, and at the same time or at different times. Thus, an isolated Mycobacterium MTC 0012 and the pharmaceutical agent may be provided as separate medicaments for administration at the same time or at different times. Preferably, an isolated Mycobacterium MTC 0012 and pharmaceutical agent are provided as separate medicaments for administration at different times. When administered separately and at different times, either an isolated Mycobacterium MTC 0012 or pharmaceutical agent may be administered first; however, it is preferable to administer an isolated Mycobacterium MTC 0012 followed by pharmaceutical agent. In addition, both drugs can be administered in the same day or at different days, and they can be administered using the same schedule or at different schedules during the treatment cycle. Preferably, the isolated Mycobacterium is administered to the patient before any anticipated traumatic event. Dose delays and / or dose reductions and schedule adjustments are performed as needed depending on individual patient tolerance to treatments. Before any anticipated traumatic event, effective amounts of Mycobacterium MTC 0012 may be administered in multiple (repeat) doses, for example two or more, three or more, four or more, five or more, ten or more, or twenty or more repeat doses, at intervals of about two weeks, or about four weeks or about eight weeks. The isolated Mycobacterium MTC 0012 may be administered to the patient via the parenteral, oral, sublingual, nasal or pulmonary route. In a preferred embodiment, the isolated Mycobacterium MTC 0012 is administered via a parenteral route selected from subcutaneous, intradermal, subdermal, intraperitoneal, intravenous and intravesicular injection. More preferably, administration by the parenteral route does not comprise injection of mycobacterial cell wall extract. In another preferred embodiment, the isolated Mycobacterium MTC 0012 is administered orally, including by suspension, tablets and the like. Liquid formulations could be administered by inhalation of lyophilized or aeorosolized microcapsules. Additional pharmaceutical vehicles could be used to control the duration of action of the preparation. They could be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization (hydroxymethylcellulose or gelatin microcapsules) in colloidal drug delivery systems (for example, liposomes, albumin microspheres, micro-emulsions, nanoparticles and nanocapsules) or in macro-emulsions. Excipients, for example, salts, various bulking agents, additional buffering agents, chelating agents, antioxidants, cosolvents and the like can be included in the final formulation. A suitable dosage schedule according to this embodiment includes administration of the isolated Mycobacterium MTC 0012 followed by further doses of said isolated MTC 0012 two weeks later and continuing every two weeks for the next three doses followed by four weeks without treatment. Thereafter, patients may receive the isolated Mycobacterium MTC 0012 every four weeks for up to 12 months or longer following the first dose given. Alternatively, dosing may involve weekly administration following the priming or initial dose. The patient who is to be exposed to an anticipated traumatic event, according to the present invention, may do so simultaneously, separately or sequentially with administration of the isolated Mycobacterium MTC 0012. Preferably the isolated Mycobacterium MTC 0012 is administered to the patient prior to the anticipated traumatic event. More specifically, the isolated Mycobacterium MTC 0012 may be administered to the patient between about four weeks and one week prior to any anticipated traumatic event. Preferably, the isolated Mycobacterium may be administered as one or more aliquots each containing an effective amount of the isolated Mycobacterium MTC 0012 which may be administered at one or more time intervals between four weeks and one week prior to any anticipated traumatic event. Even more preferably, the isolated Mycobacterium MTC 0012 may be administered as one or more aliquots each containing an effective amount of the isolated Mycobacterium MTC 0012 which may be administered at one or more time intervals between four weeks and one week before any anticipated traumatic event and / or the isolated Mycobacterium may be administered, and repeated on at least about two, four, six, eight, ten, twelve, fifteen, twenty or more occasions before and / or after any anticipated traumatic event. In one embodiment of the present invention, the isolated Mycobacterium MTC 0012 may be in the form of a medicament administered to the patient in a dosage form and / or in a schedule as set out in the examples. In an aspect of the invention, the effective amount of the isolated Mycobacterium MTC 0012 may be administered as a single dose. Alternatively, the effective amount of the isolated Mycobacterium MTC 0012 may be administered in multiple (repeat) doses, for example two or more, three or more, four or more, five or more, ten or more, or twenty or more repeat doses. Preferably, the isolated Mycobacterium MTC 0012 is administered between about four weeks and one day prior to an anticipated traumatic event, more preferably between about four weeks and one week, or about between three weeks and one week, or about between three weeks and two weeks. Administration may be presented in single or multiple doses. A container according to the invention in certain instances may be a vial, an ampoule, a syringe, capsule, tablet or a tube. In some cases, the isolated Mycobacterium MTC 0012 may be lyophilized and formulated for re-suspension prior to administration. However, in other cases, the mycobacteria are suspended in a volume of a pharmaceutically acceptable liquid. In some of the most preferred embodiments there is provided a container comprising a single unit dose of mycobacteria suspended in pharmaceutically acceptable carrier wherein the unit dose comprises about 1×106to about 1×1010Mycobacterium MTC 0012. In some very specific embodiments, the liquid comprising mycobacteria is provided in a volume of between about 0.1 ml and 10 ml, or about 0.5 ml and 2 ml. It will further be understood that in certain instances a composition comprising mycobacteria in a containment means is frozen (i.e., maintained at less than about zero degrees Celsius). The foregoing compositions provide ideal units for applications described herein. Embodiments discussed in the context of a methods and / or composition of the invention may be employed with respect to any other method or composition described herein. Thus, an embodiment pertaining to one method or composition may be applied to other methods and compositions of the invention as well. In some cases, attenuated Mycobacterium MTC 0012 is administered to specific sites on or in a subject. For example, the Mycobacterium MTC 0012 compositions according to the invention may be administered Thus, in certain instances, sites of administration of a mycobacterial composition may be near the posterior cervical, tonsillar, axillary, inguinal, anterior cervical, sub-mandibular, sub mental or superclavicular lymph nodes. Such sites of administration may be on the right side, on the left side, or on both sides of the body. In certain very specific embodiments, mycobacterial compositions are delivered close to the axillary, cervical and / or inguinal lymph nodes. For example, a dosage of the mycobacteria may be distributed into tissues adjacent to the right and left axillary lymph node and the right and left inguinal lymph nodes. In a very specific embodiment, a dosage of Mycobacterium MTC 0012 is administered to a subject by intradermal injection wherein the dosage is distributed to the axillary and inguinal on both sides of the body and wherein there are two injections (i.e., two wheals) at each site. In some further embodiments of the invention, methods of the invention involve the administration of two, three, four, five, six, seven, eight, nine, ten or more doses of Mycobacterium MTC 0012 separated by a period of one day or more. In certain preferred embodiments such separate doses will be separated by several days, one week, two weeks, one month or more. For example, methods according to the invention may comprise administering one to five doses of Mycobacterium MTC 0012 over a period of three weeks or more. In yet further embodiments, methods of the invention comprise administering one to five, one to four, one to three, one to two or two doses of Mycobacterium MTC 0012 over a period of about three weeks. Each dose administered may be the same or different dosage relative to a previous or subsequent dose administration. For example, in certain cases, it is preferred that a dosage of Mycobacterium MTC 0012 is lower than any dosage that was previously administered. Thus, in some specific cases, a dose of mycobacteria will be administered at about half of the dosage that was administered in any previous treatment. Such methods may be preferred in certain instances where the subject's immune response to the mycobacteria is greater during subsequent therapies. Thus, in certain cases, the isolated Mycobacterium may be administered a minimal number of times for example, in less than ten, nine, eight, seven, six, five, four, three or fewer separate dosage administrations. In some cases, the Mycobacterium MTC 0012 composition is administered twice. Mycobacterium MTC 0012 “pharmaceutical compositions” according to the invention can comprise an effective amount of Mycobacterium MTC 0012 typically dispersed in a pharmaceutically acceptable carrier. The phrases “pharmaceutical or pharmacologically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate. The preparation of a pharmaceutical composition that contains Mycobacterium MTC 0012 will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, Moreover, for animal (e.g., human) administration, it will be understood that parenteral preparations should meet sterility, pyrogenicity, general safety and purity standards. A specific example of a pharmacologically acceptable carrier as described herein is sterile borate-buffered saline or sterile saline solution (0.9% NaCl). As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). In a preferred embodiment, the isolated Mycobacterium MTC 0012 is administered via a parenteral route selected from subcutaneous, intradermal, subdermal, intraperitoneal, intravenous, intravesicular injection or orally. Intradermal injection enables delivery of an entire proportion of the Mycobacterium MTC 0012 composition to a layer of the dermis that is accessible to immune surveillance and thus capable of electing appropriate immune response at local lymph nodes. The various features and processes described above may be used independently of one another or may be combined in various ways. All possible combinations and sub combinations are intended to fall within the scope of this disclosure. In addition, certain method or process blocks may be omitted in some implementations. The methods and processes described herein are also not limited to any particular sequence, and the blocks or states relating thereto can be performed in other sequences that are appropriate. For example, described blocks or states may be performed in an order other than that specifically disclosed, or multiple blocks or states may be combined in a single block or state. The example blocks or states may be performed in serial, in parallel, or in some other manner. Blocks or states may be added to or removed from the disclosed example embodiments. The example systems and components described herein may be configured differently than described. For example, elements may be added to, removed from, or rearranged compared to the disclosed example embodiments. Conditional language used herein, such as, among others, “can,” “could,” “might,” “may,” “e.g.,” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements, and / or steps. Thus, such conditional language is not generally intended to imply that features, elements and / or steps are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without author input or prompting, whether these features, elements and / or steps are included or are to be performed in any particular embodiment. The terms “comprising,” “including,” “having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations, and so forth. Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. While certain example embodiments have been described, these embodiments have been presented by way of example only and are not intended to limit the scope of the inventions disclosed herein. Thus, nothing in the foregoing description is intended to imply that any particular feature, characteristic, step, module, or block is necessary or indispensable. Indeed, the novel methods and systems described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions and changes in the form of the methods and systems described herein may be made without departing from the spirit of the inventions disclosed herein. The accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of certain of the inventions disclosed herein. The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain aspects of the embodiments of the present invention. The examples are not intended to limit the invention, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the claimed invention. Indeed, while this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. EXAMPLES Example: Overview and Summary. Applicants isolated 15 novel strains of mycobacteria from soils, screened them for their immunoregulatory potential, and picked two to test in a model of stress-induced exaggeration of anxiety-like defensive behavioral responses in a rat model. Novel strain MTC 0012 was the highest-ranking strain based on an in vitro screen using murine bone marrow-derived dendritic cells and an immunoregulatory index. When tested in vivo, MTC 0012 prevented stress-induced exaggeration of anxiety-like defensive behavioral responses. Applicants developed an in vitro screening assay to determine the anti-inflammatory and immunoregulatory potential of Applicants’ strain library using GM-CSF-derived murine bone marrow-derived dendritic cells (BMDCs). Applicants also developed an algorithm to rank each strain based on their anti-inflammatory / immunoregulatory potential using ten differentially weighted input variables. In some embodiments, the input variables included one or more of the following; Il10, Il4, Il6, Il12a (encoding the IL-12p35 subunit), Il12b (encoding the IL-12p40 subunit) mRNA both individually and as ratios assessed following immune challenge with lipopolysaccharide (LPS) (more heavily weighted) or no LPS (less heavily weighted). MTC 0012 achieved the highest rank using this algorithm of anti-inflammatory / immunoregulatory bioactivity in vitro. Applicants used the algorithm to remove bias in the selection of a lead strain for in vivo testing. Indeed, MTC 0012, but not a novel mycobacterial strain with a lower ranking (MTC 0003) demonstrated stress resilience effects in Applicants’ primary behavioral test, inescapable stress (IS)-induced exaggeration of anxiety-like defensive behavioral responses in the juvenile social exploration (IS / JSE) paradigm. Applicants have demonstrated that repeated immunization with a heat-killed preparation of MTC 0012 (3 x weekly injection of 0.1 mg in 0.1 ml sterile borate-buffered saline (BBS), s.c.) prevents stress-induced increases in anxiety-like defensive behavioral responses in adult male rats based on the IS / JSE test. Importantly, however, not all mycobacteria demonstrate stress resilience effects in this model. For example, repeated immunization with a heat-killed preparation of a different novel Mycobacterium (MTC 0003) (3 x weekly injection of 0.1 mg in 0.1 ml sterile BBS, s.c.) did not prevent anxiety-like defensive behavioral responses in the IS / JSE paradigm. Also, Applicants developed an in vitro screening assay to screen strains and rank them for their immunoregulatory potential. Applicants screened MTC 0012 and MTC 0003 and MTC 0012 ranked higher than MTC 0003, which is supportive of the behavioral finding. Applicants also determined that a throughline for Applicants’ proposed mechanism of action exists based on the prevention of stress induced neuroinflammation (hippocampal Il6) and peripheral inflammation (systemic CRP). This provided an initial validation of the immunoregulatory ranking in vitro screen that translated to immunoregulatory and anti-neuroinflammatory results in vivo and promotion of stress resilience in rodents by preventing stress-induced deficits in anxiety behavior. Example 2: Isolation details and production of MTC 0012. MTC 0012 was isolated from a soil known to harbor high abundances of mycobacteria and confirmed to be novel by cultivation-independent DNA sequencing (i.e., 16S rRNA gene and hsp65 gene analyses) using previously described methods describe by Applicants. Colonies of MTC 0012 were picked and incubated in fresh liquid broth of the same media type and subcultured twice in 96-well plates to ensure that the colonies were pure. DNA was extracted from the liquid media and the identity of MTC 0012 was determined by PCR amplification and DNA sequencing for taxonomic identification and phylogenetic placement among other known mycobacteria. Stocks of MTC 0012 have been cryo-preserved in both DMSO (5%) and glycerol (10%) with aliquots maintained in liquid culture for continued production. Samples of isolated MTC 0012 have been deposited with the American Type Culture Collection (ATCC). Example 3: Novel Mycobacterium MTC 0012 strain efficacious for the prevention and treatment of PTSD. Applicants sought to determine the efficacy of oral administration of MTC 0012 in promoting an anti-inflammatory / immunoregulatory phenotype in the brain, alleviating stress- induced anxiety- and fear-like behavioral deficits, identifying potential peripheral markers of stress and inflammation to be used to optimize and tune Applicants’ immunoregulatory ranking algorithm to predict behavioral outcomes, generate a foundation for future safety and toxicology testing, generate data to contribute to Applicants’ application for an IND from the FDA to lead to Phase I clinical studies. Applicants demonstrated that repeated immunization with a heat-killed preparation of MTC 0012 (3 x weekly injection of 0.1 mg in 0.1 ml sterile borate-buffered saline (BBS), s.c.) prevents stress-induced increases in anxiety-like defensive behavioral responses in adult male rats based on the IS / JSE test (Figure 2A). Importantly, however, not all mycobacteria demonstrate stress resilience effects in this model; for example, repeated immunization with a heat-killed preparation of MTC 0003 (3 x weekly injection of 0.1 mg in 0.1 ml sterile BBS, s.c.) did not prevent anxiety-like defensive behavioral responses in the IS / JSE paradigm (Figure 2B). Also of note, MTC 0012 ranked higher than MTC 0003 on Applicants’ immunoregulation score (Figure 1), based on Applicants’ in vitro screen, providing an initial validation of the immunoregulatory ranking algorithm. Applicants know that at least some of the stress resilience effects of M. vaccae NCTC 11659 (U.S. Pat. No. 11433126, incorporated herein by reference) are dependent on the immunoregulatory effects, as depletion of Treg prevents its effects on anxiety-like defensive behavioral responses. The immunoregulatory effects of M. vaccae NCTC 11659, in turn, are thought to be mediated by effects on dendritic cells, resulting in induction of regulatory dendritic cells and differentiation of naïve T cells into Treg that drive increased production of anti- inflammatory cytokines. Additionally, M. vaccae NCTC 11659 acts on hippocampal microglia to prevent microglial priming, in association with prevention of stress-induced increases in anxiety- like defensive behavioral responses. Thus, M. vaccae NCTC 11659 induces peripheral macrophages, dendritic cells, and brain microglia to promote anti-inflammatory and immunoregulatory responses that are thought to mediate its stress resilience effects. Applicants utilized dendritic cell-based assays to screen the identified 15 novel soil-derived mycobacterial isolates which generated anti-inflammatory and immunoregulatory input variables for Applicants’ immunoregulatory ranking algorithm (Figure 1). Based on the ranking, Applicants determined MTC 0012 to be the lead candidate to test oral administration using in vivo assays designed to confirm its stress resilience promoting effects. Applicants have already confirmed that s.c. administration of MTC 0012 has stress resilience effects as assessed in the IS / JSE paradigm. For in vivo testing of oral administration of MTC 0012, Applicants can evaluate stress-induced anxiety-like defensive behavioral responses in the IS / JSE paradigm, fear extinction in an auditory- cued fear conditioning paradigm, and neuroinflammation in adult male and female Sprague Dawley rats. Notably, s.c. administration of MTC 0012 can be implemented as a positive control as Applicants have already demonstrated its efficacy in vivo (Figure 2A). TABLES Table 1: PTSD-relevant finding following immunization with Mycobacterium vaccae NCTC 11659.11For references, see Table 1 in Dawud LM, Holbrook EM, Lowry CA. Evolutionary Aspects of Diverse Microbial Exposures and Mental Health: Focus on "Old Friends" and Stress Resilience. Curr Top Behav Neurosci 2023;61:93-117.

Claims

CLAIMS What is claimed is:

1. An isolated Mycobacterium strain according to MTC 0012 (PTA-127651) deposited with the ATCC.

2. An isolated Mycobacterium strain according to MTC 0012(PTA-127651), for use in the treatment or prevention of at least one sign or symptom of posttraumatic stress disorder (PTSD) in a subject in need thereof.

3. An isolated Mycobacterium strain according to MTC 0012 (PTA-127651), for use in the treatment or prevention of at least one sign or symptom of major depressive disorder (MDD) in a subject in need thereof.

4. An isolated Mycobacterium strain according to MTC 0012 (PTA-127651), for use in the treatment or prevention of at least one sign or symptom of generalized anxiety disorder (GAD) in a subject in need thereof.

5. An isolated Mycobacterium strain according to MTC 0012 (PTA-127651), for use in the treatment or prevention of inflammation in a subject in need thereof.

6. An isolated Mycobacterium strain according to MTC 0012 (PTA-127651), for use in increasing stress resilience in a subject in need thereof.

7. An isolated Mycobacterium strain according to MTC 0012 (PTA-127651), for use in the treatment or prevention of neuroinflammation.

8. The isolated Mycobacterium for use according to any of claims 1 to 7, wherein the isolated Mycobacterium MTC 002 (PTA-127651) comprises a heat-killed Mycobacterium MTC 0012 (PTA-127651).

9. A pharmaceutical composition comprising a therapeutically effective amount of Mycobacterium MTC 0012 (PTA-127651), or its constituent parts, and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition of claim 9, wherein the therapeutically effective amount of Mycobacterium MTC 0012 (PTA-127651) comprises approximately 107to 109cells of heat-killed Mycobacterium MTC 0012 (PTA-127651).

11. The pharmaceutical composition of any of claims 9 or 10, wherein the Mycobacterium MTC 0012 (PTA-127651) or its constituent parts, is configured to be administered via the parenteral, oral, sublingual, nasal or pulmonary route.

12. The pharmaceutical composition of any of claims 9 or 10, wherein the Mycobacterium MTC 0012 (PTA-127651) or its constituent parts, is configured to be administered via the oral route.

13. The pharmaceutical composition of any of claims 11, wherein the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitonal, intravenous, or intravesicular injection.

14. A method for treating one or more symptoms of PTSD comprising administering a therapeutically effective amount of the pharmaceutical composition of any of claims 9 to 13, to a subject in need thereof.

15. The method of claim 14, wherein the one or more symptoms of PTSD are selected from disorganized or agitated behavior, problems with pain perception and pain tolerance, headache, difficult falling or staying asleep, repetitive play that expresses aspects of the trauma, frightening dreams which lack recognizable content, trauma-specific re-enactment, and symptoms of PTSD as stated in DSM-5.

16. The method of claim 14, wherein the one or more symptoms of PTSD includes at least one symptom cluster of posttraumatic stress disorder wherein the symptom cluster is selected from re- experiencing / intrusion, avoidance / numbing, and hyper-arousal.

17. A method for treating one or more symptoms of MDD comprising administering a therapeutically effective amount of the pharmaceutical compositions of any of claims 9 to 13, to a subject in need thereof.

18. A method for treating one or more symptoms of GAD comprising administering a therapeutically effective amount of the pharmaceutical composition of any of claims 9 to 13, to a subject in need thereof.

19. A method for treating one or more symptoms of inflammation comprising administering a therapeutically effective amount of the pharmaceutical composition of any of claims 9 to 13, to a subject in need thereof.

20. A method for treating one or more symptoms of neuroinflammation comprising administering a therapeutically effective amount of the pharmaceutical composition of any of claims 9 to 13, to a subject in need thereof.

21. A method for increasing stress resilience comprising administering a therapeutically effective amount of the pharmaceutical composition of any of claims 9 to 13, to a subject in need thereof.

22. The method of any of claims 14 to 22, wherein the subject is a human.

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