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Are you part of the Resistance?

No, not the Star Wars Resistance! Not the French Resistance! Are you part of the Tuberculosis resistance? Some remarkable work is being done in the Garden State to study host immunity to Mycobacterium tuberculosis by Professor Padmini Salgame and her PhD candidate, Vaishnavi Kaipilyawar at the Center for Emerging Pathogens, Rutgers-New Jersey Medical School, International Center for Public Health.


While looking at recent New Jersey research reports, I came upon their review

Infection resisters: targets of new research for uncovering natural protective immunity against Mycobacterium tuberculosis published in F1000Research. It seemed like a timely topic to inaugurate this blog considering it’s the 75th anniversary of the discovery of streptomycin - a most notable NJ achievement. Streptomycin was the first successful treatment for M. tuberculosis infection and the second of many antibiotics discovered in Nobel prize winner Selman Waksman’s laboratory at Rutgers.


The F1000Research review points out that TB is now the leading cause of death from this single infectious agent. An estimated 1.3 million TB-related deaths were reported globally among HIV-negative individuals in 2017. Nearly 23% of the world’s population is estimated to have a latent TB infection, and 5 to 10% are at risk for progressing to active disease over the course of their lifetime. Interestingly, resisters are individuals heavily exposed to M. tuberculosis but never acquire infection and diagnostically test negative (tuberculin skin test or interferon gamma release assay).


The authors conclude resisters may engage all or a combination of the following mechanisms and pathways to resist or rapidly clear M. tuberculosis infection:

(1) airway epithelium defenses: secretion of soluble factors and anti-microbial peptides by airway epithelial cells

(2) macrophage-mediated M. tuberculosis growth restriction: programmed cell death or autophagy (or both) of lung-resident and recruited alveolar macrophages leading to intracellular restriction of M. tuberculosis

(3) innate lymphoid cells: production of rapid and effective anti-mycobacterial responses by innate cell populations

(4) innate cytokine response: induction of cytokines that directly or indirectly control M. tuberculosis growth in macrophages

(5) trained immunity: molecular reprogramming of monocytes/macrophages leading to enhanced anti-mycobacterial response

(6) humoral immunity: contribution of differentially glycosylated antibodies in restricting intracellular M. tuberculosis.


M. tuberculosis strain differences also play a role. Indeed, host and strain variation together likely contribute to infection resistance as well as susceptibility to infection. Since effective vaccines are lacking and antibiotic resistance continues to develop, the involvement of the innate and trained immune responses offer new avenues for vaccine development and novel adjuncts to antibiotic therapies.


This paper beautifully points out the incredibly complex relationship between host and microbe. It prods me to further update my shallow knowledge of host immunology - essential knowledge to have in this era of the microbiome.


I had the pleasure to talk to Vaishnavi. She obtained her Bachelor of Engineering degree in Biotechnology from Manipal Institute of Technology in Karnataka, India in 2014 and then moved to Case Western Reserve in Cleveland for grad studies in pathology. She took a break for 5 mos to work as a research intern at biotech start up NovelMed Therapeutics before going back to finish her masters in 2017. After Case Western Reserve, Vaishnavi knew what she wanted to do next: study with Professor Salgame at Rutgers. Padmini Salgame is a world class researcher focusing on Mycobacterium tuberculosis and our immune response to it. Of her over 100 publications, more than ¾ have to do with this effort. Vaishnavi started her work at Rutgers in 2017.


Vaishnavi is such a stellar student that Dr Salgame (an F1000 faculty member) soon appointed her as an Associate F1000 Faculty Member to assist in recommending the most noteworthy articles in their field (see https://f1000.com/prime/thefaculty). This publication summarizes and highlights recent developments in the field of resistance to infection and how inferences from these studies could be used to identify potential avenues that can be targeted for preventive therapy.


Unsurprisingly, Vaishnavi is working on resisters. She is studying their poorly understood protective mechanisms, how they clear infection so quickly, how they remain uninfected despite repeated exposure. Vaishnavi is working with Núcleo de Doenças Infecciosas, a Center for Clinical Research and a branch of the Department of Social Medicine at Universidade Federal do Espírito Santo, Vitória, Brazil. They identify and manage the majority of TB cases detected in municipalities within the greater Vitória area. Núcleo de Doenças Infecciosas participates in the National Institute of Allergy and Infectious Diseases (NIAID) Tuberculosis Research Units Network who integrate scientific and clinical research disciplines to study aspects of human TB in endemic countries. We look forward to reading about her results in the coming months and years.


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