Role of Endosomal TLRs in Staphylococcus aureus Infection

Abstract

Identification of the receptors involved in innate immune recognition of Staphylococcus aureus, a major cause of morbidity and mortality in humans, is essential to develop alternative strategies to treat infections caused by antibiotic-resistant strains. In the current study, we examine the role of endosomal TLRs, which sense the presence of prokaryotic-type nucleic acids, in anti-staphylococcal host defenses using infection models involving genetically defective mice. Single deficiencies in TLR7, 9, or 13 resulted in mild or no decrease in host defenses. However, the simultaneous absence of TLR7, 9, and 13 resulted in markedly increased susceptibility to cutaneous and systemic S. aureus infection concomitantly with decreased production of proinflammatory chemokines and cytokines, neutrophil recruitment to infection sites, and reduced production of reactive oxygen species. This phenotype was significantly more severe than that of mice lacking TLR2, which senses the presence of staphylococcal lipoproteins. Notably, the combined absence of TLR7, 9, and 13 resulted in complete abrogation of IL-12 p70 and IFN-β responses to staphylococcal stimulation in macrophages. Taken together, our data highlight the presence of a highly integrated endosomal detection system, whereby TLR7, 9, and 13 cooperate in sensing the presence of staphylococcal nucleic acids. We demonstrate that the combined absence of these receptors cannot be compensated for by cell surface-associated TLRs, such as TLR2, or cytosolic receptors. These data may be useful to devise strategies aimed at stimulating innate immune receptors to treat S. aureus infections.

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“…Absence of TLRs results in a decreased expression of proinflammatory cytokines, a reduced production of ROS, and an increased susceptibility to the S. aureus infection …”

Exploring the Benefits of Metal Ions in Phage Cocktail for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infection

“…Specifically, TLR2 senses staphylococcal lipoproteins and TLR7, 9, and 13 recognizes staphylococcal nucleic acids. 62 At the same time, when MRSA infection occurs, its lipoprotein promotes TLR2/1 to participate in the production of IL-8. 63 Surprisingly, in our research, we found that phage cocktail supplemented with Ca 2+ and Zn 2+ could significantly increase the level of inflammatory factors in mice compared to the phage cocktail alone group, but did not lead to pathological changes of mouse organs ( Figure S5 ).…”

CodY Is a Global Transcriptional Regulator Required for Virulence in Group B Streptococcus

“…Peritoneal lavage fluids were collected at the indicated times and analyzed for cytokine levels as previously described ( Mohammadi et al, 2016 ). For in vitro cytokine induction, bone marrow-derived macrophages were obtained from 8-week-old female mice and cultured in the presence of M-CSF as previously described ( Lentini et al, 2021 ). Macrophage cultures were then stimulated for 1 h with GBS grown to the late exponential phase at the indicated multiplicities of infection (MOI).…”

“…Macrophage cultures were then stimulated for 1 h with GBS grown to the late exponential phase at the indicated multiplicities of infection (MOI). Cultures were then treated with penicillin and gentamycin (100 IU and 50 μg/ml) to kill extracellular bacteria and supernatants were collected at 18 h after culture, as previously described ( Lentini et al, 2021 ). Cytokine levels were measured in peritoneal lavage fluid samples or culture supernatants by ELISA, using Mouse TNF-alpha DuoSet ELISA DY410, Mouse IL-1 beta/IL-1F2 DuoSet ELISA DY401, Mouse CXCL2/MIP-2 DuoSet ELISA DY452, Mouse CXCL1/KC DuoSet ELISA DY453 (R&D Systems).…”