Dataset Information

Hepatitis B virus exploits C-type lectin receptors to hijack cDC1s, cDC2s and pDCs.

ABSTRACT:

Objectives

C-type lectin receptors (CLRs) are key receptors used by DCs to orchestrate responses to pathogens. During infections, the glycan-lectin interactions shape the virus-host interplay and viruses can subvert the function of CLRs to escape antiviral immunity. Recognition of virus/viral components and uptake by CLRs together with subsequent signalling cascades are crucial in initiating and shaping antiviral immunity, and decisive in the outcome of infection. Yet, the interaction of hepatitis B virus (HBV) with CLRs remains largely unknown. As HBV hijacks DC subsets and viral antigens harbour glycan motifs, we hypothesised that HBV may subvert DCs through CLR binding.

Methods

We investigated here the pattern of CLR expression on BDCA1⁺ cDC2s, BDCA2⁺ pDCs and BDCA3⁺ cDC1s from both blood and liver of HBV-infected patients and explored the ability of HBsAg to bind DC subsets through specific CLRs.

Results

We highlighted for the first time that the CLR repertoire of circulating and intrahepatic cDC2s, cDC1s and pDCs was perturbed in patients with chronic HBV infection and that some CLR expression levels correlated with plasma HBsAg and HBV DNA levels. We also identified candidate CLR responsible for HBsAg binding to cDCs (CD367/DCIR/CLEC4A, CD32/Fc?RIIA) and pDCs (CD369/DECTIN1/CLEC7A, CD336/NKp44) and demonstrated that HBsAg inhibited DC functions in a CLR- and glycosylation-dependent manner.

Conclusion

HBV may exploit CLR pathways to hijack DC subsets and escape from immune control. Such advances bring insights into the mechanisms by which HBV subverts immunity and pave the way for developing innovative therapeutic strategies to restore an efficient immune control of the infection by manipulating the viral glycan-lectin axis.

SUBMITTER: Ouaguia L

PROVIDER: S-EPMC7723857 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Hepatitis B virus exploits C-type lectin receptors to hijack cDC1s, cDC2s and pDCs.

Ouaguia Laurissa L Dufeu-Duchesne Tania T Leroy Vincent V Decaens Thomas T Reiser Jean-Baptiste JB Sosa Cuevas Eleonora E Durantel David D Valladeau-Guilemond Jenny J Bendriss-Vermare Nathalie N Chaperot Laurence L Aspord Caroline C

Clinical & translational immunology 20201208 12

<h4>Objectives</h4>C-type lectin receptors (CLRs) are key receptors used by DCs to orchestrate responses to pathogens. During infections, the glycan-lectin interactions shape the virus-host interplay and viruses can subvert the function of CLRs to escape antiviral immunity. Recognition of virus/viral components and uptake by CLRs together with subsequent signalling cascades are crucial in initiating and shaping antiviral immunity, and decisive in the outcome of infection. Yet, the interaction of ...[more]

PMID: 33312564

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Project description:Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.

Dataset Information

Hepatitis B virus exploits C-type lectin receptors to hijack cDC1s, cDC2s and pDCs.

Objectives

Methods

Results

Conclusion

Publications

Hepatitis B virus exploits C-type lectin receptors to hijack cDC1s, cDC2s and pDCs.

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