Leukotrienes Are Dispensable for Vaginal Neutrophil Recruitment as Part of the Immunopathological Response During Experimental Vulvovaginal Candidiasis

Abstract

Recruitment of polymorphonuclear neutrophils (PMNs) into the vaginal lumen is the hallmark of an acute immunopathologic inflammatory response during vulvovaginal candidiasis (VVC) caused by Candida albicans. Recurrent VVC (RVVC) remains a chronic health burden in affected women worldwide despite the use of antifungal therapy. Based on the role leukotrienes (LTs) play in promoting inflammation, leukotriene receptor antagonists (LTRAs) targeted for LTB4 (etalocib) or LTC4, LTD4, and LTE4 (zafirlukast or montelukast) have been shown to reduce inflammation of epithelial tissues. An open-label pilot study using long-term regimens of zafirlukast in women with RVVC indicated the potential for some relief from recurrent episodes. To investigate this clinical observation further, we evaluated the effects of LT antagonistic agents and LT deficiency on the immunopathogenic response in a mouse model of VVC. Results showed that mice given daily intraperitoneal injections of individual LTRAs, starting 2days prior to vaginal inoculation with C. albicans and continuing through 14days post-inoculation, had no measurable reduction in PMN migration. The LTRAs were also ineffective in reducing levels of the hallmark vaginal inflammatory markers (S100A8, IL-1β) and tissue damage (LDH) associated with the immunopathogenic response. Finally, LT-deficient 5-lipoxygenase knockout mice showed comparable levels of vaginal fungal burden and PMN infiltration to wild-type mice following inoculation with a vaginal (ATCC 96113) or laboratory (SC5314) C. albicans isolate. These results indicate that despite some clinical evidence suggestive of off-target efficacy of LTRAs in RVVC, LTs and associated signaling pathways appear to be dispensable in the immunopathogenesis of VVC.

Patients with recurrent vulvovaginal candidiasis exhibit a decrease in both the fungicidal activity of neutrophils and the proliferation of peripheral blood mononuclear cells

“…Regarding the analysis of some immunological aspects, in this study, a significant and high number of neutrophils was observed in patients with RVVC. Several studies have reported a high infiltration of PMNs at the vaginal level in RVVC patients, a factor that has been associated with the symptoms they present 31,32 . Similarly, in a study carried out by Peters et al., 33 using a mouse model, it was found that an acute inflammatory response due to PMNs occurs during vaginal infection, and this response derived from PMNs presents a strong correlation with the severity of symptoms in VVC.…”

Clinical and morphopathological assay in vulvovaginal candidiasis

“…The methods of infection of the host by the Candida fungus can be multiple and are based either on its ability to evade the host's defense mechanisms or by adhering to the surface epithelium with the subsequent formation of a biofilm and invasion by the secretion of extracellular enzymes. As mentioned, adhesion of Candida to host surfaces is essential for primary colonization of human tissues, which is a prerequisite for infections [2,7,[10][11][12][13][14][15][16][17][18]. Moreover, the production of hydrolytic enzymes induced by local infection can improve host organism adhesion, invasion and elimination of host immunological components and has a role in the acquisition of nutritional factors.…”

“…Moreover, the production of hydrolytic enzymes induced by local infection can improve host organism adhesion, invasion and elimination of host immunological components and has a role in the acquisition of nutritional factors. Hydrolytic enzymes, such as secreted aspartyl proteinases (SAPs), phospholipases (PLs) and Candida species play a role in the pathogenesis of VVC [2,[8][9][10][11][12][13][14][15][16][17][18][19].…”

“…B-lymphocytes, macrophages, plasma cells, mast cells had a much higher concentration in symptomatic patients compared to asymptomatic patients. This fact can be a consequence of the infection, but it can also be a cause of the symptoms in these patients [18][19][20]25]. The increase in the concentration of polymorphonuclear neutrophils (PMNs) at the level of the vaginal mucosa is a distinctive sign of an immunopathological inflammatory response that occurs in the case of acute infection with C. albicans.…”

“…The increase in the concentration of polymorphonuclear neutrophils (PMNs) at the level of the vaginal mucosa is a distinctive sign of an immunopathological inflammatory response that occurs in the case of acute infection with C. albicans. Yano et al are trying to explain the role played by leukotrienes in candidiasis infection, highlighting and analyzing the leukotriene receptor antagonist (LTRA), namely LTB4 (Etalocib) or LTC4, LTD4 and LTE4 (Zafirlukast or Montelukast) and have demonstrated once again the fact that these receptors reduce the inflammation of epithelial tissues [18,22,23]. Also, according to Steele & Fidel, epithelial cells play active roles in the immune responses of the vaginal mucosa thus modulating the antimicrobial activity and the production of cytokines and chemokines in response to microorganisms [21].…”