Integrating Inflammasome Signaling in Sexually Transmitted Infections

Abstract

Inflammasomes are cytosolic multiprotein platforms with pivotal roles in infectious diseases. Activation of inflammasomes results in proinflammatory cytokine signaling and pyroptosis. Sexually transmitted infections (STIs) are a major health problem worldwide, yet few studies have probed the impact of inflammasome signaling during these infections. Due to the dearth of appropriate infection models, our current understanding of inflammasomes in STIs is mostly drawn from results obtained in vitro, from distant infection sites, or from related microbial strains that are not sexually transmitted. Understanding how inflammasomes influence the outcome of STIs may lead to the development of novel and effective strategies to control disease and prevent transmission. Here we discuss and highlight the recent progress in this field.

Keywords: AIM2; IFI16; IL-18; IL-1β; NLRC4; NLRP3; cancer; caspase-1; immunopathology; inflammasome; inflammation; oncogenic; sexually transmitted infections; tumor.

Figure 1

Inflammasome Activation Mechanisms during Bacterial Sexually Transmitted Infections (STIs). Activation of the NLRP3 inflammasome occurs through the ligation of various pattern recognition receptors (PRRs). Chlamydia is taken up in a vacuole known as an inclusion, where activity of the Chlamydia type III secretion system triggers the NLRP3 inflammasome. Neisseria releases membrane lipooligosaccharide, which has been suggested to activate the NLRP3 inflammasome through a cathepsin-B-dependent pathway. Treponema surface proteins TpF1 and Td92 activate the NLRP3 inflammasome dependent on K⁺ efflux. Since our understanding of inflammasomes and their activation mechanisms is incomplete in bacterial STIs, other mechanisms may also be involved. It is also unclear whether the same mechanisms are important in vivo.

Figure 2

Key Figure: NLRP3 and NLRC4 Inflammasomes Mediate Distinct Host Immune Responses during Candida albicans Vaginal and Oral Infection (A) During vulvovaginal candidiasis, NLRP3 activation leads to IL-1β and IL-18 production. NLRP3 activity restrains fungal colonization while increasing polymorphonuclear leukocyte (PMN) flux to the vaginal tissue, through IL-1β production, leading to vaginitis. IL-18, by contrast, increases the amount of available IL-22 by decreasing the levels of IL-22-binding protein (IL-22 bp). Furthermore, IL-22 leads to phosphorylation, and thus activation, of epithelial NLRC4 and results in increased production of IL-1 receptor antagonist (IL-1Ra) thereby limiting NLRP3 activity. (B) During oropharyngeal candidiasis (thrush), epithelial NLRC4, more than NLRP3, regulates fungal colonization and PMN flux in the buccal cavity. NLRP3 activity, in both epithelial and myeloid cells, serves critical roles in protection against disseminated candidiasis.

Figure 3

Pyroptosis during HIV Infection Contributes to Disease. During HIV infection, different inflammasomes are activated in different cell types and in response to different stimuli. However, in all cell types inflammasome activation causes maturation of IL-1β and the inflammatory form of cell death, pyroptosis. Pyroptosis in CD4⁺ T cells contributes to immunodeficiency by further depleting CD4⁺ T cell numbers, whereas pyroptosis of podocytes in the kidney results in HIV-associated nephropathy.