Herpes simplex virus-binding IgG traps HSV in human cervicovaginal mucus across the menstrual cycle and diverse vaginal microbial composition

Abstract

IgG possesses an important yet little recognized effector function in mucus. IgG bound to viral surface can immobilize otherwise readily diffusive viruses to the mucin matrix, excluding them from contacting target cells and facilitating their elimination by natural mucus clearance mechanisms. Cervicovaginal mucus (CVM) is populated by a microbial community, and its viscoelastic and barrier properties can vary substantially not only across the menstrual cycle, but also in women with distinct microbiota. How these variations impact the "muco-trapping" effector function of IgGs remains poorly understood. Here we obtained multiple fresh, undiluted CVM specimens (n = 82 unique specimens) from six women over time, and employed high-resolution multiple particle tracking to quantify the mobility of fluorescent Herpes Simplex Viruses (HSV-1) in CVM treated with different HSV-1-binding IgG. The IgG trapping potency was then correlated to the menstrual cycle, and the vaginal microbial composition was determined by 16 s rRNA. In the specimens studied, both polyclonal and monoclonal HSV-1-binding IgG appeared to consistently and effectively trap HSV-1 in CVM obtained at different times of the menstrual cycle and containing a diverse spectrum of commensals, including G. vaginalis-dominant microbiota. Our findings underscore the potential broad utility of this "muco-trapping" effector function of IgG to reinforce the vaginal mucosal defense, and motivates further investigation of passive immunization of the vagina as a strategy to protect against vaginally transmitted infections.

Robust antigen-specific tuning of the nanoscale barrier properties of biogels using matrix-associating IgG and IgM antibodies

“…Such weak bonds imply a single antibody is likely incapable of crosslinking a pathogen or particle to mucus. Nevertheless, this weak affinity allows the antibodies to undergo rapid diffusion in hydrogel [26,[39][40][41], and thus quickly accumulate on the surface of nanoparticles and pathogens. In turn, once a critical threshold of antibodies is reached, the array of bound antibodies ensures there is at least one bond between the biogel matrix and nanoparticle-antibody complex at any moment in time, resulting in nanoparticle trapping with permanent avidity [26].…”

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

“…A recently discovered yet little recognized effector function of virus-specific IgG is to crosslink viruses to the mucin mesh [ [69] , [70] , [71] , [72] , [73] , [74] ], leading to their immobilization in AM ( Fig. 2 ).…”

Learning from past failures: Challenges with monoclonal antibody therapies for COVID-19

“…Given the large quantities of endogenous IgG that are already present in airway mucus secretions, inhaled mAb therapies are also likely to be well tolerated. Finally, by harnessing Fc-mucin interactions [ [61] , [62] , [63] , [64] ], inhaled mAbs may also facilitate rapid elimination of viruses from infected airways through mucus clearance mechanisms including muco-ciliary mucus transport and/or cough clearance [ 65 ], thereby physical eliminating the viral antigens that drive pulmonary hyperinflammation. Consistent with the aforementioned advantages of direct delivery into the lung as well as the apical route of infection and spread of these viruses, prior work has shown that human mAbs delivered directly into the lung are highly efficacious [ 58 , 59 , 66 , 67 ], and more effective than the same mAbs introduced systemically [ 58 , 59 ].…”