Mannan-binding lectin modulates the response to HSV-2 infection

Abstract

SUMMARYViruses have developed numerous strategies to escape recognition by the immune system. However, some viruses such as herpes simplex virus-2 (HSV-2) are recognized by initiators of the complement system, e.g. mannan-binding lectin (MBL). To study the effects of MBL deficiency during viral infection we have chosen a model of generalized HSV-2 infection. We infected MBL-A and MBL-C double knockout mice (DKO) with HSV-2 via the intraperitoneal (i.p.) route. DKO mice cleared HSV-2 from the liver less efficiently than the comparable wild-type animals. The impairment to effectively neutralize HSV-2 correlated with compromised liver function as measured by increased plasma levels of alanineamino transferase. No differences in the viral burden were found in other organs such as spleen or brain. Thus, MBL-mediated protection was limited to the effects of preservation of liver homeostasis. Reconstitution with recombinant human MBL before and during the HSV-2 infection dramatically lowered the viral titres in the liver. Taken together, the data show that MBL modulates the response to HSV-2 in mice by affecting neutralization of the virus. To analyse if MBL plays a role in establishment and progression of human HSV-2 infection we analysed MBL levels in the serum samples from asymptomatic (virus-exposed people who have never displayed symptoms of HSV-2 infection) and symptomatic HSV-2 patients (people with recurrent HSV-2 infections). We found that the frequency of the MBL deficiency ( < 100 ng/ml) was higher in the symptomatic group and significantly different from that in the asymptomatic group ( P = 0·0369). This suggests that lack of MBL-mediated complement activation increases susceptibility to viral infection.

Deficiency of Mannose-Binding Lectin Greatly Increases Susceptibility to Postburn Infection withPseudomonas aeruginosa

“…Other patient populations did not show such a relationship (56 -58) and thus it appears that the effect of MBL deficiency is revealed only under certain clinical conditions. In our studies aimed at clarifying the role of MBL, we have found that MBL null mice are susceptible to infection with S. aureus (24) and HSV-2 (25). The present study adds P. aeruginosa to the list of pathogens that show increased infectivity in MBL-deficient animals.…”

“…We postulated that MBL, a serum protein, might play a key role as an innate immune molecule able to limit the systemic spread of locally infecting pathogens in burned tissue. This idea was informed by the knowledge that MBL is deployed quickly to sites of infection as has been shown in the lung (23) in addition to our previous work demonstrating that MBL null mice are highly susceptible to infection with Staphylococcus aureus (24) and HSV-2 (25).…”

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

“…This was proposed by Kruse et al (131), who demonstrated that patients with MBL levels <100 ng/mL had a higher abortion rate. Some urogenital infections such as vulvovaginitis, herpes simplex virus-2 infection, vulvovaginal candidiasis and vestibulitis appear to be linked to low MBL levels in comparison to healthy controls (132)(133)(134). Downstream complement deficiencies are typically associated with recurrent invasive infections of Neisseria meningitidis and gonorrhea (135).…”

Mannose-Binding Lectin Genotypes and Susceptibility to Epstein-Barr Virus Infection in Infancy

“…Furthermore, promoter polymorphisms in the MBL2 gene (X and Y) influence the level of functional MBL (18). MBL-deficient individuals are more susceptible to a range of infections, especially in early infancy before the maturation of the adaptive immune system (14), and MBL is known to modulate the response to viral infections, including herpesviruses (3,4,23). Thus, MBL increases neutralization of herpes simplex virus type 2 (HSV-2), MBL deficiency is more prevalent in symptomatic HSV-2 patients (4), and MBL-deficient individuals are at greater risk of recurrent HSV-2 infection (23).…”