About Us

The Bogunovic lab  focuses on the study of human immunogenetics. We aim to improve understanding of the human immune system by studying  1) individuals with rare auto-inflammatory syndromes  2) individuals with severe clinical presentations of infections usually causing mild or no clinical disease and 3) genetic basis of immune response in neoplasm. To dissect these phenotypes we use genomic, genetic, molecular biology, cellular biology, immunology and clinical tools.

The hypothesis of the lab is that inter-individual variability in immune responses (in auto-inflammatory syndromes, infections or neoplasm) can also be explained by the immune genetic composition of the host.


ISG15 deficiency 

We have recently identified null mutation in ISG15 in children with autosomal recessive ISG15 deficiency.  ISG15 deficient individuals present with persistently high levels of mRNA for select IFN-α/β-inducible genes (ISGs) in their blood cells when tested ex vivo, mimicking Aicardi-Goutières syndrome (AGS) and susceptibility to environmental mycobacteria. Mechanistically, we found that the lack of intracellular free ISG15 resulted in inadequate stability of USP18, a potent negative regulator of IFN-α/β signaling and a bona fide deISGylating enzyme. Unlike Isg15-/- mice, which show high susceptibility to a wide range of viruses, humans deficient for ISG15 show no overt susceptibility to viral disease and in fact, may have an enhanced capacity to control viral infections. To date, we have defined essential roles for free extracellular ISG15 in immunity against mycobacteria (Bogunovic et. al, Science), and for free intracellular ISG15, as a negative regulator of IFN-α/β signaling (Zhang et. al, Nature) and suggested that ISG15 deficiency at least in vitro results in augmented control of viral infections as compared to WT individuals ( Speer et. al, Nature Communications).

USP18 deficiency

We have recently identified 5 children with complete USP18 deficiency (in collaboration with Dr. Manchini at Erasmus University, The Netherlands) and detailed the molecular mechanisms behind the Type I IFN inflammation. Importantly these children presented with a severe perinatal onset of inflammation  (Meuwissen et. al  Journal of Experimental Medicine) suggestive of intrauterine infection, yet not infectious origin was identified, leading to diagnosis of Pseudo-TORCH syndrome. USP18 has both enzymatic (acting as a deISGylating enzyme) and negative regulatory activity (prevent IFN mediated inflammation).We continue to study these and other individuals with similar disease presentations looking to unveil novel genetic and molecular mechanisms behind this syndrome.

Interestingly, the role for ISGylation in humans remains elusive. We now aim at better understanding the role for ISGylation in human setting. To do so, we utilize a number of genetic models we have discovered or generated, allowing us to mechanistically assess the questions of ISGylation, and deISGylation as they pertain to ISG15 and USP18 biology.

Human genetic susceptibility to Listeria monocytogenes

We are studying the pathogenesis of central nervous system infections with the foodborne pathogen Listeria monocytogenes (neurolisteriosis). In immunocompetent individuals, infection with Listeria monocytogenes generally results in minor gastrointestinal problems. In rare cases, infection with Listeria monocytogenes may cause invasive infections, resulting in meningitis in this population, with significant mortality and morbidity. We seek to unveil host genetic causes of disease in this patient population.

Human immune genetics of cancer

As with autoimmune and infectious disease, human immune response to neoplasm is vastly individual both in disease progression and susceptibility to given immune therapy. We seek to unveil both host and neoplasm genetics as determinants of responsiveness to immune therapy, thereby paving a way for personalized medicine approaches of both boosting and choosing the correct therapy.

By aiming to illuminate the elusive pathogenesis of these diseases, we are hoping to lay the foundation for a novel and paradigm-shifting approach to the rational design of both preventative medicine (vaccines and genetic counseling) and treatments beyond current standards.