Characterizing the innate and adaptive responses of immunized mice toBordetella pertussisinfection usingin vivoimaging and transcriptomic analysis

Abstract

18Bordetella pertussis (B. pertussis) is the causative agent of pertussis (whooping cough). 19 Since the 1990s, pertussis has re-emerged in the United States despite an estimated 20 95% vaccine coverage. Our goal was to characterize neutrophil responses and gene 21 expression profiles of murine lungs in the context of vaccination and B. pertussis 22 challenge. We utilized a bioluminescent neutrophil mouse model (NECre luc) to track 23 neutrophil recruitment. NECre luc mice were immunized with whole cell vaccine (WCV), 24 acellular vaccine (ACV), or a truncated adenylate cyclase toxoid (RTX) vaccine. 25 Neutrophil recruitment was measured in live mice across time and corroborated by flow 26 cytometry and other data. WCV immunized mice showed signs of neutrophilia in response 27 to B. pertussis challenge. Mice immunized with either ACV or WCV cleared the challenge 28 infection; however immunization with RTX alone was not protective. RNA sequencing 29 revealed distinctive gene expression profiles for each immunization group. We observed 30 an increase in expression of genes associated with responses to infection, and changes 31 in expression of distinct genes in each vaccine group, providing a complex view of the 32 immune response to B. pertussis infection in mice. This study suggests that combination 33 of immunological analysis with transcriptomic profiling can facilitate discovery of pre-34 clinical correlates of protection for vaccine development.35 36 37 38 39 41Pertussis is a human disease primarily caused by a respiratory infection of the Gram-42 negative pathogen Bordetella pertussis (B. pertussis). The hallmark of pertussis is a distinctive 43 whooping cough. What is surprising about pertussis is that the cause of the cough has never been 44 elucidated, which highlights the fact that there are many under-researched aspects of this 45 disease. Aerosolized B. pertussis bacterium are inhaled and adhere to airway respiratory 46 epithelial cells through bacterial adhesins such as filamentous hemagglutinin (FHA), fimbriae and 47 pertactin 1 . After colonization B. pertussis express multiple toxins including pertussis toxin (PT) 48 and adenylate cyclase toxin (ACT). B. pertussis releases PT, which dysregulates the immune 49 response through ADP-ribosylation of the G-protein α-subunit of cytokine receptors present on a 50 range of leukocytes 2-5 . The secretion of PT has long range effects, ACT is thought to act locally 51 on host cells by converting ATP into supraphysiological levels of cAMP, further dysregulating the 52 host immune response 6 . 53In the 1940s, an effective whole cell vaccine (WCV) was developed and as a result, basic research 54 efforts on B. pertussis decreased. The WCVs were highly reactogenic and caused prolonged and 55 unusual crying after administration, hyporesponsivness, and febrile convulsions 7-9 . These issues 56 led to the development of acellular vaccines (ACV), known today as DTaP/Tdap (hereafter 57 referred to as ACV). The ACVs utilize an alum adjuvant and induce a Th2 response ...

Next-Generation Pertussis Vaccines Based on the Induction of Protective T Cells in the Respiratory Tract

“…IL-17 produced by γδ T cells and Th17 cells helps to promote recruitment of neutrophils to the respiratory tract. Neutrophil numbers peak in the lung at 5-7 days post challenge in mice, and have the capacity to phagocytose and kill B. pertussis , but are not essential for clearance of bacteria from the lungs during primary infection [ 49 , 50 ]. They do, however, play an important role in the protection of immune mice from reinfection, which is believed to be due to bacterial killing via antibody-mediated phagocytosis [ 49 ].…”

Diet induced obesity and type 2 diabetes drives exacerbated sex-associated disease profiles in K18-hACE2-mice challenged with SARS-CoV-2

“…Bulk RNAseq analysis of infected mouse tissues allows for simultaneous pathogen and host transcriptomic analysis (72). We have previously used similar techniques to characterize mouse and bacterial gene expression during infection (73)(74)(75). After evaluation of the viral transcriptomics of SARS-CoV-2 challenge in DIO mice, lung tissue RNA from non-challenged, challenged, DIO, or normal diet mice was used to characterize the host transcriptomic responses to SARS-CoV-2.…”

Long-Term Analysis of Pertussis Vaccine Immunity to Identify Potential Markers of Vaccine-Induced Memory Associated With Whole Cell But Not Acellular Pertussis Immunization in Mice

“…Furthermore, the mouse model has allowed researchers to better understand mucosal responses and neonatal responses to pertussis (24,25). Recent work has identified several new immune factors associated with pertussis vaccination and intranasal challenge using the mouse model including: T resident memory cells, secretory IgAs, and interleukin-6, to name a few (23,(26)(27)(28)(29). Despite some caveats, such as lack of audible coughing, this model recapitulates disease manifestation, continues to provide novel findings, and remains a relevant model for pertussis vaccine development.…”