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Dengue and the Lectin Pathway of the Complement System.

ABSTRACT: Dengue is a mosquito-borne viral disease causing significant health and economic burdens globally. The dengue virus (DENV) comprises four serotypes (DENV1-4). Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF). Complement system activation induces inflammation and tissue injury, contributing to disease pathogenesis. However, in asymptomatic or primary infections, protective immunity largely results from the complement system's lectin pathway (LP), which is activated through foreign glycan recognition. Differences in N-glycans displayed on the DENV envelope membrane influence the lectin pattern recognition receptor (PRR) binding efficiency. The important PRR, mannan binding lectin (MBL), mediates DENV neutralization through (1) a complement activation-independent mechanism via direct MBL glycan recognition, thereby inhibiting DENV attachment to host target cells, or (2) a complement activation-dependent mechanism following the attachment of complement opsonins C3b and C4b to virion surfaces. The serum concentrations of lectin PRRs and their polymorphisms influence these LP activities. Conversely, to escape the LP attack and enhance the infectivity, DENV utilizes the secreted form of nonstructural protein 1 (sNS1) to counteract the MBL effects, thereby increasing viral survival and dissemination.

SUBMITTER: Kraivong R

PROVIDER: S-EPMC8310334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mannose-binding lectin (MBL) is a key soluble pathogen recognition protein of the innate immune system that binds specific mannose-containing glycans on the surfaces of microbial agents and initiates complement activation via the lectin pathway. Prior studies showed that MBL-dependent activation of the complement cascade neutralized insect cell-derived West Nile virus (WNV) in cell culture and restricted pathogenesis in mice. Here, we investigated the antiviral activity of MBL in infection by dengue virus (DENV), a related flavivirus. Using a panel of naïve sera from mouse strains deficient in different complement components, we showed that inhibition of infection by insect cell- and mammalian cell-derived DENV was primarily dependent on the lectin pathway. Human MBL also bound to DENV and neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Experiments with human serum from naïve individuals with inherent variation in the levels of MBL in blood showed a direct correlation between the concentration of MBL and neutralization of DENV; samples with high levels of MBL in blood neutralized DENV more efficiently than those with lower levels. Our studies suggest that allelic variation of MBL in humans may impact complement-dependent control of DENV pathogenesis. IMPORTANCE Dengue virus (DENV) is a mosquito-transmitted virus that causes a spectrum of clinical disease in humans ranging from subclinical infection to dengue hemorrhagic fever and dengue shock syndrome. Four serotypes of DENV exist, and severe illness is usually associated with secondary infection by a different serotype. Here, we show that mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Moreover, we observed a direct correlation with the concentration of MBL in human serum and neutralization of DENV infection. Our studies suggest that common genetic polymorphisms that result in disparate levels and function of MBL in humans may impact DENV infection, pathogenesis, and disease severity.

Project description:BACKGROUND:This exploratory study investigated the time-course of lectin complement pathway (LCP) initiators in cerebrospinal fluid (CSF) and plasma in patients with subarachnoid hemorrhage (SAH), as well as their relationship to delayed cerebral ischemia (DCI) and functional outcome. METHODS:Concentrations of ficolin-1, ficolin-2, ficolin-3, and mannose-binding lectin (MBL) were analyzed in CSF and plasma from patients with SAH. Samples were collected daily from admission until day 9 (CSF; N_PATIENTS = 63, n_SAMPLES = 399) and day 8 (plasma; N_PATIENTS = 50, n_SAMPLES = 358), respectively. Twelve neurologically healthy patients undergoing spinal anesthesia and 12 healthy blood donors served as controls. The development of DCI during hospitalization and functional outcome at 3?months (modified Rankin Scale) were registered for patients. RESULTS:On admission, CSF levels of all LCP initiators were increased in SAH patients compared with healthy controls. Levels declined gradually over days in patients; however, a biphasic course was observed for ficolin-1. Increased CSF levels of all LCP initiators were associated with a poor functional outcome in univariate analyses. This relationship persisted for ficolin-1 and MBL in multivariate analysis after adjustments for confounders (age, sex, clinical severity, distribution and amount of blood on CT-imaging) and multiple testing (1.87?ng/mL higher in average, 95% CI, 1.17 to 2.99 and 1.69?ng/mL higher in average, 95% CI, 1.09 to 2.63, respectively). In patients who developed DCI compared with those without DCI, CSF levels of ficolin-1 and MBL tended to increase slightly more over time (p_interaction = 0.021 and 0.033, respectively); however, no association was found after adjustments for confounders and multiple testing (p-adj_interaction = 0.086 and 0.098, respectively). Plasma ficolin-1 and ficolin-3 were lower in SAH patients compared with healthy controls on all days. DCI and functional outcome were not associated with LCP initiator levels in plasma. CONCLUSION:Patients with SAH displayed elevated CSF levels of ficolin-1, ficolin-2, ficolin-3, and MBL. Increased CSF levels of ficolin-1 and MBL were associated with a poor functional outcome. TRIAL REGISTRATION:This study was a retrospective analysis of samples, which had been prospectively sampled and stored in a biobank. Registered at clinicaltrials.gov ( NCT01791257 , February 13, 2013, and NCT02320539 , December 19, 2014).

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Dengue and the Lectin Pathway of the Complement System.

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