Igor Kramnik obtained his PhD from the Central Institute for Tuberculosis Research of the Russian Academy of Sciences in Moscow, Russia. There he started his studies of lung-specific aspects of anti-tuberculosis immunity and discovered myeloid suppressor cells within pulmonary TB lesions. He continued to study host immunity to mycobacteria at the Center for the Study of Host Resistance at McGill University in Montreal and the Albert Einstein College of Medicine in the Bronx, New York, with Professors Emil Skamene and Barry Bloom, respectively. In 1999 he was recruited to the faculty at the Department of Immunology and Infectious Diseases at the Harvard School of Public Health in Boston. In 2009 he became an Investigator at the National Emerging Infectious Disease Laboratory and joined the Pulmonary Center at Boston University. During this period, he developed a mouse model of pulmonary TB that develop human-like necrotic TB granulomas and used this model to reveal the genetic control and mechanisms driving the necrotic pathology. His current research is focused on further dissecting the interplay of the host and bacterial factors leading to immunopathology in TB and the development of host-directed approaches to improve the outcomes of TB therapies.
TB is now the leading infectious cause of death globally due to a single microbe with 10 million incident cases of TB worldwide in 2017, associated with 1.3 million deaths. The emergence and spread of antibiotic resistant strains of Mycobacterium tuberculosis (Mtb) in human populations has become a global emergency. Despite the recent approval of three new drugs, there remains an urgent need to develop more effective treatment regiments, including mechanistic host-directed therapies (HDT) aiming at boosting immunity and preventing lung tissue damage. This requires a more advanced understanding of the mechanisms of TB pathogenesis, as well as the development of animal models mechanistically reflecting various forms of human TB.
The formation of the necrotic TB granuloma is a core virulence mechanism which enables pathogen survival, sanctuary from immune clearance mechanisms, and transmission. Why certain individuals are able to generate controlled granulomatous inflammation without disease progression, while others do not, remains unclear. Recent observations establish an association of TB progression with the upregulation of type I interferon (IFN-I) pathways in humans, but mechanisms for how this cytokine contribute to TB susceptibility and immunopathology remain poorly defined.
Mouse models have been instrumental in dissecting essential mechanisms of host resistance to Mtb, as well as in pre-clinical testing of TB drugs and vaccines. The development of a mouse model that develop human-like organized necrotic TB granulomas in the lungs allowed us to study specific mechanisms of Mtb-inflicted lung damage. We have identified a mouse genetic locus sst1 (supersusceptibility to tuberculosis 1) that controls the necrotization and have shown that mice that carry the sst1 susceptibility allele were not immunodeficient and developed adequate T cell-mediated immunity. In subsequent studies we revealed an aberrant response of the mutant macrophages to TNF, which was dominated by the hyperactivity of IFN-I-mediated pathways. We have found that IFN-I drives diverse downstream pathways that compromise host immunity via cell intrinsic and secretory mechanisms. A novel secretory mechanism in the sst1 susceptible mice was revealed by the Vance team who found that the IFN-I-driven upregulation of the IL-1 receptor antagonist (IL-1Ra) led to systemic increase in susceptibility to virulent Mtb (Ji et al., 2019). Our studies reveal an intrinsic IFN-I driven mechanisms in TNF-stimulated sst1 susceptible macrophages that led to metabolic dysregulation and escalating integrated stress response (ISR) via PKR activation (Bhattacharya et al, 2018; BioRxiv 499467). Interestingly elevations of ISR markers have already been found to be strongly upregulated in human necrotic granulomas specifically in cellular layers close to necrotic centers of the TB granulomas (Semoin, et al., 2010). Taken together these results point to elevated IFN-I responses as a key driver of necrosis within TB lesions and reveal distal immunologic mechanisms responsible for systemic and local immune dysregulation within TB lesions of otherwise immunocompetent hosts.
Thus, the sst1-mediated susceptible phenotype in mice that bears striking morphological similarities to human TB lesions, also provided novel insights into mechanisms of necrotization within TB lesions that parallel progression of the human disease. These data allowed us to test novel host-directed therapies that specifically target the above mechanisms of necrosis in TB lesions using the mouse model. These novel “necrosis-directed” therapies could potentially synergize with antibiotics and therapeutic vaccines to combat the re-emergent threat of TB.
