Dengue

The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients.

 Dengue is a mosquito-borne viral infection caused by dengue virus (DENV) with an estimated 390 million dengue infections worldwide every year and over 2.5 billion people at risk of the infection1. Dengue cases in South-East Asian countries are exponentially increasing with an annual average of 386,000 cases between 2001 and 20102. Vietnam is a country with high dengue incidence and hyperendemic transmission of DENV. The outbreaks are generally larger and more common in southern provinces of Vietnam, with incidence peaking between June and October3,4.

Four distinct serotypes of the virus cause dengue (DENV-1, DENV-2, DENV-3 and DENV-4)5. DENVs circulate in Vietnam with a predominance of the DENV-1 and DENV-2 serotypes and DENV-2 appear to cause more severe conditions than the other serotypes6. The clinical manifestation of an acute DENV infection varies from mild febrile illness lasting approximately 4–7 days to life-threatening severe dengue haemorrhagic fever and dengue shock syndrome (DHF/DSS), characterized by plasma leakage, fluid accumulation, respiratory distress, severe bleeding, or organ impairment. The complex interplay of human innate and adaptive cellular immune responses with the virus is believed to influence the clinical course of DENV infection7. Recovery from infection provides lifelong immunity against the serotype which has caused the disease episode. However, cross-immunity to the other serotypes after recovery is only partial and short-term. Subsequent infections by other serotypes increase the risk of developing dengue haemorrhagic fever and such secondary infections are mediated by antibody-dependent immune enhancement (ADE)7,8.

Complement proteins, innate immune recognition molecules are activated either by classical, alternative or the lectin complement pathways during the early phase of infection9. The lectin complement pathway is triggered when the lectin proteins, namely the mannose-binding lectin (MBL) and/or the ficolins (FCN) bind to the pathogen recognition receptors on the surface of pathogens. Subsequently, a sequential enzyme cascade is triggered where MBL-associated protein 2 (MASP2) and other complement proteins (C5b-9) are activated leading to the formation of the membrane attack complex which eventually ends with opsonization, lysis, activation of inflammatory responses and/or clearance of immune complexes9. Human MBL encoded by MBL2 gene is located on chromosome 10 and three single nucleotide polymorphisms (SNPs) in exon1 at codons 52 (MBL2*D), 54 (MBL2*B), and 57 (MBL2*C) respectively, interfere with the formation of higher MBL oligomers, causing alterations in functional activity of the protein and their circulating levels10,11,12. In addition, three promoter polymorphisms (positions, − 550, − 221 and + 4) were shown to regulate plasma MBL levels12. The MBL2*B, MBL2*C or MBL2*D mutant alleles are referred to as MBL2*O, whereas the wildtype is addressed as MBL2*A. MBL deficiency and MBL2 polymorphisms have been shown to be associated with several infectious and autoimmune diseases13,14.

MBL was shown to neutralize DENV via complement-dependent and independent mechanisms, suggesting a significant role of MBL in the pathogenesis of dengue15. A previous study has indicated direct complement restriction of DENV infection via MBL recognition of the high-mannose glycans of DENV envelope proteins16. In addition, MBL2 polymorphisms have been shown to be associated with dengue severity in Brazilian and Thai populations17,18,19. The above studies have investigated only the contribution of MBL2 polymorphisms and MBL serum levels. The present study utilizing a Vietnamese study group has investigated not only MBL serum levels and MBL2 variants but has also looked at associations of several downstream complement proteins of the complement pathway, namely C2, C4b, C5, C5a, C9, factor D and factor I with DENV infection.

Link: https://www.nature.com/articles/s41598-020-71947-2