Complement Opsonization Promotes Herpes Simplex Virus 2 Infection of Human Dendritic Cells

Abstract

Herpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of immune responses. In genital mucosa, the primary target cells for HSV-2 infection are epithelial cells, but resident immune cells, such as dendritic cells (DCs), are also infected. DCs are the activators of the ensuing immune responses directed against HSV-2, and the aim of this study was to examine the effects opsonization of HSV-2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV-2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV-2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV-1- or HSV-2-specific antibodies more or less abolished HSV-2 infection of DCs. Our results clearly demonstrate the importance of studying HSV-2 infection under conditions that ensue in vivo, i.e., conditions under which the virions are covered in complement fragments and complement fragments and antibodies, as these shape the infection and the subsequent immune response and need to be further elucidated.IMPORTANCE During HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. The dendritic cells are activators of the immune responses directed against HSV-2, and the aim of this study was to examine the effects of complement alone or complement and antibodies on HSV-2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses. Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV-2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV-2 pathogenesis.

Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response

“…Our lab has verified that opsonizing in seminal fluid generates similar opsonization to the one obtained when using serum [115,134]. In addition, incubating HIV with purified C3 protein together with Factor D, Factor B, Ca2+ and Mg2+ at similar concentrations as found in vivo [102] gave a very similar effect on dendritic cell inflammatory and antiviral responses compared with incubating HIV in serum (unpublished observation).…”

“…Importantly, our previous studies show that when it comes to dendritic cells, complement fragments on both HIV and HSV2 interact mainly with CR3, as cells from SLE patients with nonfunctional CD11b have similar responses to both free and complement opsonized virus [115,125].…”

“…gC also binds iC3b at the same regions as it binds C3b [114]. These complement fragments then remain on the viral surface [115].…”

“…Genetic modification through CRISPR requires the use of sgRNA which is likely to have a similar effect on antiviral signaling to siRNA. To verify the dependency of observed effects on CR3 in our system, we have successfully used cells from individuals with genetic variants that render this receptor non-functional [115,138].…”

Acute and prolonged complement activation in the central nervous system during herpes simplex encephalitis

“…In contrast to bacterial infections, clinical data of complement activation is scarce for viral CNS infections. However, complement activity in response to such infections has recently been demonstrated in cell cultures as well as in animal studies (Chen and Reiss, 2002;Crisci et al, 2016;Fuchs et al, 2011;Kotwal et al, 2014;Rhoades et al, 2011;Speth et al, 2002). Moreover, invading microorganisms have developed different strategies to evade the complement participation in combating their invasion (Veerhuis et al, 2011).…”