Periodic Reporting for period 1 - LUNG-BIM (Induction of B cell immunity in the lung mucosa)
Berichtszeitraum: 2019-04-01 bis 2021-03-31
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.
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.
The results obtained during this project are presented in the technical report. As these data is part of a manuscript that we are submitting in September 2021 and is confidential, I prefer not to include it here.
FINAL PERIOD:
The results obtained with this study were published in Immunity in 2022. Reference:
Gregoire C, Spinelli L, Villazala-Merino S, Gil L, Holgado MP, Moussa M, Dong C, Zarubica A, Fallet M, Navarro JM, Malissen B, Milpied P*, Gaya M* (*corresponding author). Viral infection engenders bona fide and bystander subsets of lung-resident memory B cells through a permissive mechanism. Immunity 2022, 55 (7):1216-1233.e9.
Furthermore, I presented these results at the B cell Keystone 2023 in Colorado and in several research institutes such as Crick Institute (London, UK), University of Edinburgh (UK), Rennes University (France), Brest University (France), DCBiol meeting (Marseillle, france), EMBO YIP meeting (Milan, Italy).
Inserm further prepared a press release of our article that you can find here:
https://presse.inserm.fr/en/highly-effective-memory-b-cells-localized-in-the-lungs/60604/
FINAL PERIOD:
The results obtained with this study were published in Immunity in 2022. Reference:
Gregoire C, Spinelli L, Villazala-Merino S, Gil L, Holgado MP, Moussa M, Dong C, Zarubica A, Fallet M, Navarro JM, Malissen B, Milpied P*, Gaya M* (*corresponding author). Viral infection engenders bona fide and bystander subsets of lung-resident memory B cells through a permissive mechanism. Immunity 2022, 55 (7):1216-1233.e9.
Furthermore, I presented these results at the B cell Keystone 2023 in Colorado and in several research institutes such as Crick Institute (London, UK), University of Edinburgh (UK), Rennes University (France), Brest University (France), DCBiol meeting (Marseillle, france), EMBO YIP meeting (Milan, Italy).
Inserm further prepared a press release of our article that you can find here:
https://presse.inserm.fr/en/highly-effective-memory-b-cells-localized-in-the-lungs/60604/
- The generation of broadly neutralizing antibodies against highly variable or emerging pathogens, such as HIV, influenza, and Zika virus, has recently gained much attention for the development of effective vaccines that confer broad and long-lasting immunity. Recent discoveries show that lung-persistent germinal centers extend the breadth of antibody specificity and provide cross-protection against microbial escape mutants. Therefore, it is crucial to understand how B cell immunity is triggered in the respiratory airways during infection. To my knowledge, this is the first study that will investigate how B cell encounter of pathogens takes place in the lung mucosa.
- The project not only aims to identify which immune cells function as antigen reservoirs in the lung mucosa but also pursue to uncover the mechanisms that these cells use to deliver intact viral particles to specific B cells.
- This work will highlight that anatomy, and not just molecular components, matter in the efforts to develop new vaccine strategies that can induce broadly neutralizing antibody responses against highly variable pathogens. For instance, future flu vaccines might be delivered intranasally instead of subcutaneously to induce better responses.
FINAL PERIOD:
Our research suggests that there are two subpopulations of memory B cells expressing different genes, known as “bona fide” and “bystanders”, with the “bona fide” cells having a particular affinity for the virus that triggered their appearance. In the event of new encounters with this pathogen, they immediately differentiate into plasma cells and secrete highly specific antibodies against the virus.mConversely the “bystanders” do not directly recognize the virus but bind thanks to a specific receptor to the immune complexes formed by the antibodies that are produced by the “bona fides”. The “bystanders” can therefore enable cross-reactions by increasing the response of different “bona fide” populations against several types of viruses. “What we have is a two-tier system that enables a synergistic effect and increases the efficacy of the anti-viral memory response in the lungs”
These findings could in fact form the basis for new research into the way vaccines are administered. The hypothesis is that by intranasal vaccination, we could mimic the natural entry pathway of the virus, mobilize these lung memory B cells to block the virus as soon as it reaches the respiratory tract in the event of an infection. In this way, we could combat severe forms and also better protect against infection.
- The project not only aims to identify which immune cells function as antigen reservoirs in the lung mucosa but also pursue to uncover the mechanisms that these cells use to deliver intact viral particles to specific B cells.
- This work will highlight that anatomy, and not just molecular components, matter in the efforts to develop new vaccine strategies that can induce broadly neutralizing antibody responses against highly variable pathogens. For instance, future flu vaccines might be delivered intranasally instead of subcutaneously to induce better responses.
FINAL PERIOD:
Our research suggests that there are two subpopulations of memory B cells expressing different genes, known as “bona fide” and “bystanders”, with the “bona fide” cells having a particular affinity for the virus that triggered their appearance. In the event of new encounters with this pathogen, they immediately differentiate into plasma cells and secrete highly specific antibodies against the virus.mConversely the “bystanders” do not directly recognize the virus but bind thanks to a specific receptor to the immune complexes formed by the antibodies that are produced by the “bona fides”. The “bystanders” can therefore enable cross-reactions by increasing the response of different “bona fide” populations against several types of viruses. “What we have is a two-tier system that enables a synergistic effect and increases the efficacy of the anti-viral memory response in the lungs”
These findings could in fact form the basis for new research into the way vaccines are administered. The hypothesis is that by intranasal vaccination, we could mimic the natural entry pathway of the virus, mobilize these lung memory B cells to block the virus as soon as it reaches the respiratory tract in the event of an infection. In this way, we could combat severe forms and also better protect against infection.