Global Health Colloquium

 

Richard Hernandez

A proteo-genetic approach to define acid-dependent changes in Mycobacterium marinum secretion

Pathogenic mycobacteria, including M. tuberculosis, represent a major global health burden. During infection, the macrophage serves as their primary niche. Many bacterial pathogens are engulfed by the macrophage, trapped in a phagosome and destroyed once that phagosome fuses with a lysosome. Pathogenic mycobacteria subvert this immune response by escaping the phagosome using ESAT-6 secretion system-1 (ESX-1). ESX-1 is a type VII secretion system that secretes substrates that lyse phagosomal membranes and allow mycobacteria to escape and proliferate in the cytoplasm. Strains lacking ESX-1 do not escape and are attenuated. Phagosomes vary depending on the immunological activation state of the macrophage. In cell culture models, Mycobacteria-containing phagosomes remain near-neutral (pH 6.2) in resting macrophages, but acidify (pH 4.5-5.0) in activated macrophages. Until now, the field has only considered ESX-1 in the context of neutral pH. How the ESX-1 system functions under acidic pH is still unclear. There is a critical need to define ESX-1 secretion at acidic pH to fully understand how mycobacteria employ this system during infection. To address this gap, I took a proteo-genetic approach to studying ESX-1 function in Mycobacterium marinum, a well-established model for studying this secretion system. By generating targeted genetic knockouts and quantifying secreted proteins through liquid chromatography–tandem mass spectrometry, I demonstrate that M. marinum switches which substrates it secretes based on the pH of its environment. This will help understand which ESX-1 substrates perform an acid-specific function.

Kathryn Curry

Developing Novel Monoclonal Antibodies Against Human Cytomegalovirus Infection

Human cytomegalovirus (HCMV) is estimated to infect 50-80% of the U.S. population by age 40. While normally asymptomatic in healthy individuals, HCMV poses a serious threat to immuno-compromised groups. This cohort includes solid organ transplant patients, those living with AIDS, pregnant mothers, and individuals on immunosuppressives. With infected mothers, there is a higher risk of infants contracting congenital (c)HCMV, a leading cause of non-hereditary birth defects. Antivirals cannot be taken by all groups affected and there is currently no FDA approved vaccine. To combat these limitations, monoclonal antibody (mAb) therapy has been viewed as both a potential treatment and preventive measure due to high specificity and low toxicity. However, once HCMV infects a cell, it can internalize antibodies and destroy them.

Thus, there is a critical need for development of a treatment option for HCMV that counteracts this immune evasion mechanism.

Jalynn Murray

Understanding a-Gal Syndrome: An Examination of Tick Salivary Biomolecules

α-Galactose Syndrome (AGS) is a pathogenic tick-borne disorder mediated by immunoglobulin E (IgE) antibody, which causes a delayed anaphylactic reaction to non-primate mammalian components including meats, dairy products, and gelatin-containing products. AGS is also becoming increasingly more prevalent as the Center for Disease Control estimates the possibility that as many as 450,000 Americans may have the sensitivity (CDC 2025). This would make AGS the tenth most common allergy among adults in the United States. AGS is often underdiagnosed and there is little education surrounding the transmission pathway. There is also currently no treatment for AGS, and the management strategy includes complete avoidance of all α-galactose containing products (Flaherty et al. 2017). Our goal is to bridge the gap in understanding the transmission pathway of AGS, through study of tick salivary biomolecules, including the characterization of glycans containing a-Gal residues.