Upper and lower respiratory infections represent one of the major medical concerns due to their rapid ability to spread in a community over a short period of time. The fast widespread of respiratory agents can contribute to pandemic and epidemic outbreaks as observed several times during human history. In fact, the 1918 Spanish flu pandemic, cause by an unusual strain of H1N1 influenza virus was one of the deadliest natural disasters in the last centuries, resulting in around 100 million deaths, five percent of the world's population at that time. At present, respiratory infections remain the deadliest communicable disease and the highest cause of mortality in low-income countries. According to the World Health Organization (WHO), lower and upper respiratory infections caused 3.0 million deaths worldwide in 2016. The highest contagious respiratory infection is caused by influenza A virus. Annual epidemics of influenza infection results in 5 to 10 million cases every year and a significant morbidity and mortality inthe young, elderly, and immunodeficient, remaining a serious threat to public health. Vaccination is widely considered one of the greatest medical achievements for preventing infectious diseases. The basis for most currently licensed human vaccines relies on the induction of high affinity antibodies by antigen-specific B cells that can neutralize infectious pathogens in case of re-exposures. The widespread immunity that vaccination conveys has led to worldwide eradication of smallpox and the elimination of diseases such as polio and diphtheria from most parts of the world. However, the generation of vaccines against influenza virus fail to provide long-lasting protection to different strain variants due to the virus’s rapid antigenic variation. Owing to the lack of cross-protective vaccines, there is an immediate medical need for new therapeutic approaches that can effectively protect us from influenza. A deeper understanding of the cellular and molecular mechanisms of B cell activation in response to respiratory infection is thus key in the development of next-generation vaccines.
FINAL PERIOD: Lung-resident memory B cells (MBCs) provide localized protection against reinfection in respiratory airways. The biology of these cells remains largely unexplored. For my proposal, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. We found that two main transcriptionally distinct subsets of MBCs colonized the lung peribronchial niche after infection. These subsets arose from different progenitors and were both class switched, somatically mutated, and intrinsically biased in their differentiation fate toward plasma cells. Combined analysis of antigen specificity and B cell receptor repertoire segregated these subsets into "bona fide" virus-specific MBCs and "bystander" MBCs with no apparent specificity for eliciting viruses generated through an alternative permissive process. Thus, I found that diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire.
