Vaccination with Mycoplasma pneumoniae membrane lipoproteins induces IL-17A driven neutrophilia that mediates Vaccine-Enhanced Disease

Abstract

Bacterial lipoproteins are an often-underappreciated class of microbe-associated molecular patterns with potent immunomodulatory activity. We previously reported that vaccination of BALB/c mice with Mycoplasma pneumoniae (Mp) lipid-associated membrane proteins (LAMPs) resulted in lipoprotein-dependent vaccine enhanced disease after challenge with virulent Mp, though the immune responses underpinning this phenomenon remain poorly understood. Herein, we report that lipoprotein-induced VED in a mouse model is associated with elevated inflammatory cytokines TNF-α, IL-1β, IL-6, IL-17A, and KC in lung lavage fluid and with suppurative pneumonia marked by exuberant neutrophilia in the pulmonary parenchyma. Whole-lung-digest flow cytometry and RNAScope analysis identified multiple cellular sources for IL-17A, and the numbers of IL-17A producing cells were increased in LAMPs-vaccinated/Mp-challenged animals compared to controls. Specific IL-17A or neutrophil depletion reduced disease severity in our VED model—indicating that Mp lipoproteins induce VED in an IL-17A-dependent manner and through exuberant neutrophil recruitment. IL-17A neutralization reduced levels of TNF-α, IL-1β, IL-6, and KC, indicating that IL-17A preceded other inflammatory cytokines. Surprisingly, we found that IL-17A neutralization impaired bacterial clearance, while neutrophil depletion improved it—indicating that, while IL-17A appears to confer both maladaptive and protective responses, neutrophils play an entirely maladaptive role in VED. Given that lipoproteins are found in virtually all bacteria, the potential for lipoprotein-mediated maladaptive inflammatory responses should be taken into consideration when developing vaccines against bacterial pathogens.

B cells oppose Mycoplasma pneumoniae vaccine enhanced disease and limit bacterial colonization of the lungs

“…In addition, investigations of CD4 + T cell behavior in mouse models of the related pathogen M. pulmonis revealed a similar decrease in lung pathology after depletion of CD4 + T cells 61 , further implicating Th cells in the dysregulated response. Exposure to M. pneumoniae antigen has been reported to induce the expression of inflammatory cytokines associated with the Th17 lineage, including IL-17A and IL-23 26 , 62 – 65 , and IL-17A has been shown to exacerbate lung pathology in mice infected with Mycoplasma pulmonis 66 . The Th17/Treg axis is dynamic, and heavily influenced by anti-inflammatory cytokines during T cell exposure to antigen.…”

The trehalose glycolipid C18Brar promotes antibody and T-cell immune responses to Mannheimia haemolytica and Mycoplasma ovipneumoniae whole cell antigens in sheep

“…Studies have demonstrated that IL-17 contributes to the clearance of bacterial pathogens such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Streptococcus pneumoniae in the respiratory tract [77,78]. During M. haemolytica infection high levels of IL-17 in the lungs can lead to the uncontrolled infiltration of neutrophils and has been attributed to lung damage in mice, goats, and big horn sheep [26,79,80], although IL-17 does not seem to cause any damage in domestic sheep [80]. These studies suggest that IL-17 could help in clearing bacterial pathogens, particularly during early stages of respiratory infection, thus providing mucosal immunity during pneumonia.…”

Novel antigenic proteins of Mycoplasma synoviae as potential vaccine candidates

“…Many factors affect the efficacy of the vaccine, including the antigen itself. Some surface lipoproteins can aggravate the disease caused by mycoplasma infection 41 . RS00275 is also a kind of surface lipoprotein.…”