Protozoan-Viral-Bacterial Co-Infections Alter Galectin Levels and Associated Immunity Mediators in the Female Genital Tract

Abstract

Co-infections with sexually transmittable pathogens are common and more likely in women with disturbed vaginal bacteriome. Among those pathogens, the protozoan parasite Trichomonas vaginalis (TV) is most common after accounting for the highly persistent DNA viruses human papillomavirus (HPV) and genital herpes. The parasitic infection often concurs with the dysbiotic syndrome diagnosed as bacterial vaginosis (BV) and both are associated with risks of superimposed viral infections. Yet, the mechanisms of microbial synergisms in evading host immunity remain elusive. We present clinical and experimental evidence for a new role of galectins, glycan-sensing family of proteins, in mixed infections. We assessed participants of the HIV Epidemiology Research Study (HERS) at each of their incident TV visits (223 case visits) matched to controls who remained TV-negative throughout the study. Matching criteria included age, race, BV (by Nugent score), HIV status, hysterectomy, and contraceptive use. Non-matched variables included BV status at 6 months before the matched visit, and variables examined at baseline, within 6 months of and/or at the matched visit e.g. HSV-2, HPV, and relevant laboratory and socio-demographic parameters. Conditional logistic regression models using generalized estimating equations calculated odds ratios (OR) for incident TV occurrence with each log10 unit higher cervicovaginal concentration of galectins and cytokines. Incident TV was associated with higher levels of galectin-1, galectin-9, IL-1β and chemokines (ORs 1.53 to 2.91, p <0.001). Galectin-9, IL-1β and chemokines were up and galectin-3 down in TV cases with BV or intermediate Nugent versus normal Nugent scores (p <0.001). Galectin-9, IL-1β and chemokines were up in TV-HIV and down in TV-HPV co-infections. In-vitro, TV synergized with its endosymbiont Trichomonasvirus (TVV) and BV bacteria to upregulate galectin-1, galectin-9, and inflammatory cytokines. The BV-bacterium Prevotella bivia alone and together with TV downregulated galectin-3 and synergistically upregulated galectin-1, galectin-9 and IL-1β, mirroring the clinical findings of mixed TV–BV infections. P. bivia also downregulated TVV+TV-induced anti-viral response e.g. IP-10 and RANTES, providing a mechanism for conducing viral persistence in TV-BV co-infections. Collectively, the experimental and clinical data suggest that galectin-mediated immunity may be dysregulated and exploited by viral–protozoan–bacterial synergisms exacerbating inflammatory complications from dysbiosis and sexually transmitted infections.

Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner

“…Further studies with larger sample sizes are needed to confirm our results and to define changes in middle-aged and perimenopausal groups, also at high risk for infection in the US [ 82 ]. Finally, we have described a number of factors that are modified in a high-SCFA environment that could be relevant for inflammation and antiviral defense; however, additional factors and underlying mechanisms for the described changes remain to be investigated, such as, for example, the potential role of galectin-9 modifications in inflammatory cytokine/chemokine release and neutrophil recruitment [ 83 , 84 , 85 , 86 ].…”

Mixed Vaginitis in the Third Trimester of Pregnancy Is Associated With Adverse Pregnancy Outcomes: A Cross-Sectional Study

“…In vivo studies in another mixed infection model of aerobic and anaerobic bacteria have found that compared with MRSA-infected mice that are not infected with Prevotella intermedia supernatant, mice infected with hospital-acquired methicillin-resistant S. aureus (HA-MRSA) and P. intermedia supernatant had a significantly lower survival rate, a significantly higher lung bacterial load, and significantly higher expression of α-hemolysin in the lungs ( Yamashita et al., 2020 ). A study on the inflammatory factors in vaginal secretions of patients with mixed infection of BV + trichomoniasis found that the inflammatory factors, regulated on activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-3α, MIP-1β, monocyte chemotactic protein, and galectin-1, were elevated, indicating an obvious inflammatory phenotype in mixed infections ( Fichorova et al., 2021 ).…”

The L-Rhamnose Biosynthetic Pathway in Trichomonas vaginalis: Identification and Characterization of UDP-D-Glucose 4,6-dehydratase

“…We cannot definitively conclude that this protein has a key role in the last reduction step since it is not found in the closely related T. foetus , which is expected to have a functional L-Rha pathway [ 27 ], and in H. meleagridis , a related trichomonad parasite that causes histomonosis in poultry [ 36 ]. The high similarity of TvRED (TVAG_357160) to 4-keto reductases from Bacteroidetes, which are often present as commensal organisms in the gut and vaginal microbiota [ 11 , 37 ], suggests the possibility of its acquisition after the radiation of the trichomonad lineage through a recent LGT, which is known to be an important event shaping the Tv genome [ 38 ].…”

“…TvLG mutants display reduced adherence and cytotoxicity to human ectocervical cells [ 7 , 8 ]. Moreover, the TvLG triggers an inflammatory response, leading to a selective cytokine upregulation in female reproductive tract epithelial cells, and it is also implicated in evasion from the host innate immunity [ 9 , 10 , 11 , 12 ].…”