Lipid moieties of Mycoplasma pneumoniae lipoproteins are the causative factor of vaccine-enhanced disease

Mara, Arlind B.; Gavitt, Tyler D.; Tulman, E. R.; Geary, Steven J.; Szczepanek, Steven M.

doi:10.1038/s41541-020-0181-x

Cited by 14 publications

(18 citation statements)

References 28 publications

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“…Researchers in the 1960’s attempted to develop vaccines for M. pneumoniae using formalin-inactivated whole pathogen, but these efforts were stymied by the observation that some vaccinated individuals experienced enhanced clinical symptoms upon subsequent infection in comparison to unvaccinated control subjects 23 . This finding, later termed Vaccine-Enhanced Disease (VED), has been recapitulated in mouse models of M. pneumoniae infection, and has stood as a roadblock to successful vaccine development for several decades 24 – 27 . Prior exposure to live or inactivated M. pneumoniae followed by subsequent challenge consistently leads to increased lung pathology characterized by enhanced leukocyte infiltration and perivascular/peribronchiolar cuffing 24 , 27 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Development of an effective vaccine for Mycoplasma pneumoniae has been hindered by reports of Vaccine Enhanced Disease (VED) in test subjects vaccinated and challenged in studies conducted in the 1960s. The exact mechanism of disease exacerbation has yet to be fully described, but host immune responses to Lipid-Associated Membrane Proteins (LAMPs) lipoprotein lipid moieties have been implicated. LAMPs-induced exacerbation appears to involve helper T cell recall responses, due in part to their influence on neutrophil recruitment and subsequent inflammatory responses in the lung. Herein, we characterized the functions of host B cell responses to M. pneumoniae LAMPs and delipidated-LAMPs (dLAMPs) by conducting passive transfer and B cell depletion studies to assess their contribution to disease exacerbation or protection using a BALB/c mouse model. We found that antibody responses to M. pneumoniae LAMPs and dLAMPs differ in magnitude, but not in isotype or subclass. Passive transfer, dLAMP denaturation, and monoclonal antibody studies indicate that antibodies do not cause VED, but do appear to contribute to control of bacterial loads in the lungs. Depletion of B cells prior to LAMPs-vaccination results in significantly enhanced pathology in comparison to B cell competent controls, suggesting a possible regulatory role of B cells distinct from antibody secretion. Taken together, our findings suggest that B cell antibody responses to M. pneumoniae contribute to, but are insufficient for protection against challenge on their own, and that other functional properties of B cells are necessary to limit exacerbation of disease in LAMPs-vaccinated mice after infection.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Additionally, Huang and colleagues have indicated that the lipidassociated membrane proteins of U. parvum and U. urealyticum induce U937 cell cycle arrest in the G1 phase through a p21-dependent but p53-independent pathway [274], suggesting that this signaling pathway is highly correlated with the inflammatory and protective effects in ureaplasmal diseases. Interestingly, a recent report has indicated that the lipid moiety of M. pneumoniae lipoprotein is a causative factor of vaccine-enhanced disease, which overcomes the roadblock of vaccine development [14]. This suggests that the development of a vaccine should balance the maintenance of its immune-stimulatory activity and reduce the side effects caused by the lipid moiety.…”

Section: Membrane Lipoproteinsmentioning

confidence: 99%

“…Mycoplasmas can also express various pathogenic enzymes such as lipolytic enzymes, peptidases, phosphatases, ecto-ATPases, cytotoxic nucleases and nucleotidases, that are considered important mycoplasma pathogenic factors [12,13]. Furthermore, some inherent components located at the mycoplasma cell membrane, such as lipids, membrane lipoproteins, and even superantigens produced by Mycoplasma arthritidis, could trigger an inflammatory response through various strategies (Figure 1) [14][15][16]. Although several questions remain unanswered, significant progress has been made in identifying the virulence factors by which mycoplasmas interact with and subsequently damage the host cells.…”

Section: Introductionmentioning

confidence: 99%

Infection strategies of mycoplasmas: Unraveling the panoply of virulence factors

Chen

Qin

et al. 2021

Virulence

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Mycoplasmas, the smallest bacteria lacking a cell wall, can cause various diseases in both humans and animals. Mycoplasmas harbor a variety of virulence factors that enable them to overcome numerous barriers of entry into the host; using accessory proteins, mycoplasma adhesins can bind to the receptors or extracellular matrix of the host cell. Although the host immune system can eradicate the invading mycoplasma in most cases, a few sagacious mycoplasmas employ a series of invasion and immune escape strategies to ensure their continued survival within their hosts. For instance, capsular polysaccharides are crucial for anti-phagocytosis and immunomodulation. Invasive enzymes degrade reactive oxygen species, neutrophil extracellular traps, and immunoglobulins. Biofilm formation is important for establishing a persistent infection. During proliferation, successfully surviving mycoplasmas generate numerous metabolites, including hydrogen peroxide, ammonia and hydrogen sulfide; or secrete various exotoxins, such as communityacquired respiratory distress syndrome toxin, and hemolysins; and express various pathogenic enzymes, all of which have potent toxic effects on host cells. Furthermore, some inherent components of mycoplasmas, such as lipids, membrane lipoproteins, and even mycoplasmagenerated superantigens, can exert a significant pathogenic impact on the host cells or the immune system. In this review, we describe the proposed virulence factors in the toolkit of notorious mycoplasmas to better understand the pathogenic features of these bacteria, along with their pathogenic mechanisms.

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“…Two biological replicates of Lag3 À/À and three of WT cells were assessed in triplicate per condition. All samples were prepared for proteomic analysis using filter-aided sample preparation, as previously described, with a few modifications (16,17). Briefly, a 200-mg protein whole cell lysate aliquot was removed and diluted with UA buffer (8 M urea in 0.1 M Tris HCl [pH 8.5]), and protein Cys residues were reduced using 25 mM DTT in UA for 1.5 h at 37 C. Directly afterward, the sample solutions were loaded onto a Microcon YM-10 10 kDa molecular mass cutoff filter (Thermo Fisher Scientific) previously conditioned with intact BSA (Sigma-Aldrich) and washed thoroughly.…”

Section: Adoptive Ot-ii Cell Transfer Experimentsmentioning

confidence: 99%

Lymphocyte Activation Gene-3 Regulates Dendritic Cell Metabolic Programing and T Cell Priming Function

Cruz

Giri

Turro

et al. 2021

The Journal of Immunology

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Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-α and decreased IL-10 secretion from LAG3-deficient human B lymphoblasts. The hypothesis tested in this study was that Lag3 deficiency in dendritic cells (DCs) would significantly affect cytokine expression, alter cellular metabolism, and prime naive T cells to greater effector differentiation. Experimental approaches used included differentiation of murine bone marrow–derived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD4+Lag3+/+ donor cells into wild-type (WT) C57BL/6 and Lag3−/− recipient mice, and ex vivo measurements of IFN-γ from cultured splenocytes. Results showed that Lag3−/− BMDCs secreted more TNF-α, were more glycolytic, used fewer fatty acids for mitochondrial respiration, and glycolysis was significantly reduced by exogenous IL-10 treatment. Under basal conditions, RNA sequencing revealed increased expression of CD40 and CD86 and other cytokine-signaling targets as compared with WT. Whole cell proteomics identified a significant number of proteins up- and downregulated in Lag3−/− BMDCs, with significant differences noted in exogenous IL-10 responsiveness compared with WT cells. Ex vivo, IFN-γ expression was significantly higher in Lag3−/− mice as compared with WT. With in vivo adoptive T cell and in vitro BMDC:T coculture experiments, Lag3−/− BMDCs showed greater T cell effector differentiation and proliferation, respectively, compared with WT BMDCs. In conclusion, Lag3 deficiency in DCs is associated with an inflammatory phenotype that provides a plausible mechanism for increased cardiovascular disease risk in humans with LAG3 deficiency.

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Lipid moieties of Mycoplasma pneumoniae lipoproteins are the causative factor of vaccine-enhanced disease

Cited by 14 publications

References 28 publications

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

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

Infection strategies of mycoplasmas: Unraveling the panoply of virulence factors

Lymphocyte Activation Gene-3 Regulates Dendritic Cell Metabolic Programing and T Cell Priming Function

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