The following abstracts will be presented at the conference on September 21st and 22nd. Additional abstracts to follow shortly!

Qu Biologics’ Goal: Curing Crohn’s Disease by Restoring Innate Immunity

Qu Biologics has developed a novel Crohn’s disease treatment designed to restore innate immune function to clear the dysbiosis and infection which underlies Crohn’s disease (CD). Current immunotherapies for CD treat the end result of the disease by suppressing the adaptive immune system. This approach is associated with significant side effects, limited effectiveness in many people with CD, and requires life-long immunosuppression. There is growing evidence that what underlies CD is innate immune suppression, resulting in an inability to clear pathogenic bacteria, with resultant chronic infection and dysbiosis. Qu’s Site Specific Immunomodulator (SSI), QBECO, derived from inactivated E. coli, restores innate immune function in the gastrointestinal (GI) tract, clearing bacterial infection and dysbiosis, and thus, removing the underlying trigger for the overreactive adaptive immune response.  Unlike current CD treatments, QBECO is designed to safely and effectively normalize immune function through multiple important immunological pathways simultaneously in a manner compatible with the body’s normal immune response. Importantly, unlike the adaptive immune system, which is highly specific, the innate immune response is non-specific and thus, once restored, the innate immune system is able to clear a wide variety of pathogens, including bacteria, viruses and fungi, not just E. coli, from which QBECO is derived. Derived from inactivated bacteria, QBECO is self-administered by simple subcutaneous injection. By treating the disease in this very different way, Qu’s goal is sustained remission or cure, off of all medications after a 6-12 month treatment course. Qu has completed Phase 2 studies in CD and UC with compelling results. A follow-on Phase 2 CD study is underway.

 

Case report: Chronic neurologic and psychiatric illness in a middle-aged women, blood culture positive for an atypical Mycobacteria.

A middle-aged woman with a history of depression and hypothyroidism will be presented with an 8-year history of unusual symptoms including one-sided allodynia, paresthesias, intractable headaches, worsening depression, arthralgias, periodic night sweats and irritable bowel symptoms. Early on in her illness, a unifying diagnosis was not found and treatments included a therapeutic trial of steroids which caused a steroid psychosis and led to inpatient psychiatric hospitalization culminating in 25+ ECT treatments, 18 months ago a buffy coat blood culture was positive for an atypical Mycobacteria. A three drug antibiotic regimen was begun with dramatic sustained improvement.

 

From Achilles’ heel to a peptide-based vaccine for Mycobacterium paratuberculosis the causative agent of paratuberculosis in ruminants and humans.

WC Davis¹, GS Abdellrazeq^1,2, MM Elnaggar^1,2, CD Souza³, JP Bannantine⁴, J Hwang³

1. Dept Vet Micro/Pathol, Washington State University, Pullman, WA, U.S.
2. Dept Microbiol, Faculty Veterinary Medicine, Alexandria University, Egypt
3. Dept Veterinary Clinical Sciences, Washington State University, Pullman, WA, U.S.
4. National Animal Disease Center, USDA-Agricultural Research Service, Ames, IA, U.S.

Objective: Studies were conducted ex vivo to demonstrate the potential efficacy for a peptide based vaccine for paratuberculosis, caused by Mycobacterium avium subsp paratuberculosis (Map).

Methods: Two ex vivo assays were developed and used to study the functional activity of CD4 and CD8 T cells proliferating in response to stimulation with dendritic cells (DC) pulsed with a major membrane protein, MMP, expressed by Map.

Results: Two rounds of stimulation with MMP-pulsed DC incorporated into a nanoparticle vector elicited a consistent CD4, CD8 T cell proliferative response. Analysis of the response showed responding CD8 T cells developed the ability to kill Map present in macrophage target cells infected with Map.

Conclusion: MMP shows potential for development of an efficacious vaccine.

 

Controlling the switch between environmental and virulence programs of Mycobacterium avium

Infection by nontuberculous mycobacteria (NTM) is increasing in patients with chronic respiratory diseases, including cystic fibrosis. There are major gaps in our understanding of the mechanisms of NTM pathogenesis, how to diagnose these infections, and even simply when to treat infected individuals. Identification of new therapeutics, diagnostics, and biomarkers of pathogenic potential are key for developing better therapeutic interventions. We took advantage of new genetic tools, in combination with powerful models of infection, to identify pathogenic mechanisms of Mycobacterium avium, the most prevalent NTM pathogen in the United States. We took advantage of its unique ability to interconvert between two colony morphotypes, smooth transparent (SmT) and smooth-opaque (SmO), when grown on solid media. Consistent with the strong clinical correlation between virulence and bacteria in the SmT morphotype, our preliminary results revealed that the SmT morphotype is able to replicate and establish infection in mouse infections whereas the SmO morphotype is cleared from murine organs. However, SmO bacteria are more fit for growth in axenic culture than SmT. Differential gene expression analysis by RNAseq revealed that SmT and SmO have divergent transcriptional profiles with functional enrichment in the SmO morphology for two-component regulatory systems and in the SmT morphology for fatty acid metabolism. We performed a transposon mutagenesis of SmT and SmO to identify genes enabling M. avium to interconvert between colony morphotypes. These mutagenesis screens revealed toxin-anti-toxin systems and genes involved in carbon flux as critical for the colony morphology switch. Together, our results support the hypothesis that these the two M. avium morphotypes reflect bacteria that have activated one of two genetic programs, one with greater fitness in the environment (SmO) and the other that promotes infection (SmT). Furthermore, we hypothesize that this cell fate decision is governed by environmental cues and bacterial signal transduction pathways that allow cells to “switch” between these two genetic programs. Understanding how to prevent transition to the virulence program, or how to identify the pathogenic potential of bacteria at the earliest stages of infection, may provide novel ways to prevent or treat NTM infections.