PROJECT SUMMARY Lower respiratory tract infections are the leading cause of mortality for children under 5 years old1,2. Although exposure to respiratory pathogens is common, very few children have severe or life-threatening disease3. A better understanding of this inter-individual variability may allow us to more effectively prevent or treat serious infections in those most at-risk. Inborn errors of immunity (IEI) are rare monogenic diseases that serve as ‘experiments of nature’ to pinpoint genes and immune pathways critical to defense against specific pathogens. However, despite the clear value that IEI research offers, IEI are vastly underdiagnosed. We investigated a consanguineous family with two children affected by severe and recurrent bacterial respiratory infections including Streptococcus pneumoniae. By whole exome sequencing we discovered these patients were homozygous for the novel mutation N10Kfs*17 in TANK. We showed that this mutation leads to a complete loss of TANK protein expression, indicating that we identified the first ever reported cases of TANK deficiency. TANK is an adaptor protein assumed to participate in signaling pathways downstream of several immune receptors4,5. However, its function in the human immune system remains largely unknown. To tackle this knowledge gap, we performed in depth immunophenotyping of these patients’ samples. We found that TANK is critical for B cell activation and differentiation, and production of immunoglobulins. Thus, we hypothesize that TANK is critical for B cell activation and that genetic variants altering its pathway cause human diseases. Capitalizing on the unique scientific opportunity that these patients offer we will characterize in depth the immunological consequences of TANK deficiency (Aim 1). TANK has been implicated in the non-canonical NF-κB pathway and mutations that cause similar clinical and immunological consequences affect this pathway6–8. Hence, Aim 2 will focus on deciphering the role of TANK in non-canonical NF-κB pathway signaling4,5. We have shown that we can leverage knowledge from rare and high-impact genetic variants that cause IEI to understand how more frequent genetic variants contribute to common immunological and infectious diseases9,10. Therefore, in Aim 3 we will take advantage of our access to several large biorepositories of genetic data linked to de-identified electronic health records to ascertain the impact of genetic variants in the TANK pathway on human disease phenotypes. The work proposed in this application has far reaching clinical and immunological implications. We will characterize the function of TANK in the human immune system, particularly its role in B cell activation and differentiation. Our findings will showcase a novel mechanism of non-canonical NF-κB activation mediated by TANK. Finally, we will unravel the consequences of genetic variants in TANK and its pathway in human diseases. In summary, by studying a rare genetic disease we have...