Association of the Mannose-Binding Lectin 2 BB Genotype with COVID-19-Related Mortality

Objectives Sars-CoV-2 acute infection is clinically heterogeneous, ranging from asymptomatic cases to patients with a severe, systemic clinical course. Among the involved factors age and preexisting morbidities play a major role; genetic host susceptibility contributes to modulating the clinical expression and outcome of the disease. Mannose-binding lectin is an acute-phase protein that activates the lectin-complement pathway, promotes opsonophagocytosis and modulates inflammation, and is involved in several bacterial and viral infections in humans. Understanding its role in Sars-CoV-2 infection could help select a better therapy. Methods We studied MBL2 haplotypes in 419 patients with acute COVID-19 in comparison to the general population and related the haplotypes to clinical and laboratory markers of severity. Results We recorded an enhanced frequency of MBL2 null alleles in patients with severe acute COVID-19. The homozygous null genotypes were significantly more frequent in patients with advanced WHO score 4–7 (OR of about 4) and related to more severe inflammation, neutrophilia, and lymphopenia. Conclusions Subjects with a defective MBL2 genotype (i.e., 0/0) are predisposed to a more severe acute Sars-CoV-2 infection; they may benefit from early replacement therapy with recombinant MBL. Furthermore, a subset of subjects with the A/A MBL genotype develop a relevant increase of serum MBL during the early phases of the disease and develop a more severe pulmonary disease; in these patients, the targeting of the complement may help. Therefore, COVID-19 patients should be tested at hospitalization with serum MBL analysis and MBL2 genotype, to define the optimal therapy.

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Unraveling the impact of SARS-CoV-2 mutations on immunity: insights from innate immune recognition to antibody and T cell responses

Bayarri-Olmos,

Sutta,

Rosbjerg

et al. 2024

Front. Immunol.

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Throughout the COVID-19 pandemic, the emergence of new viral variants has challenged public health efforts, often evading antibody responses generated by infections and vaccinations. This immune escape has led to waves of breakthrough infections, raising questions about the efficacy and durability of immune protection. Here we focus on the impact of SARS-CoV-2 Delta and Omicron spike mutations on ACE-2 receptor binding, protein stability, and immune response evasion. Delta and Omicron variants had 3–5 times higher binding affinities to ACE-2 than the ancestral strain (KDwt = 23.4 nM, KDDelta = 8.08 nM, KDBA.1 = 4.77 nM, KDBA.2 = 4.47 nM). The pattern recognition molecule mannose-binding lectin (MBL) has been shown to recognize the spike protein. Here we found that MBL binding remained largely unchanged across the variants, even after introducing mutations at single glycan sites. Although MBL binding decreased post-vaccination, it increased by 2.6-fold upon IgG depletion, suggesting a compensatory or redundant role in immune recognition. Notably, we identified two glycan sites (N717 and N801) as potentially essential for the structural integrity of the spike protein. We also evaluated the antibody and T cell responses. Neutralization by serum immunoglobulins was predominantly mediated by IgG rather than IgA and was markedly impaired against the Delta (5.8-fold decrease) and Omicron variants BA.1 (17.4-fold) and BA.2 (14.2-fold). T cell responses, initially conserved, waned rapidly within 3 months post-Omicron infection. Our data suggests that immune imprinting may have hindered antibody and T cell responses toward the variants. Overall, despite decreased antibody neutralization, MBL recognition and T cell responses were generally unaffected by the variants. These findings extend our understanding of the complex interplay between viral adaptation and immune response, underscoring the importance of considering MBL interactions, immune imprinting, and viral evolution dynamics in developing new vaccine and treatment strategies.

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Association of the Mannose-Binding Lectin 2 BB Genotype with COVID-19-Related Mortality

Cited by 3 publications

References 33 publications

Spotlight on contributory role of host immunogenetic profiling in SARS-CoV-2 infection: Susceptibility, severity, mortality, and vaccine effectiveness

Spotlight on contributory role of host immunogenetic profiling in SARS-CoV-2 infection: Susceptibility, severity, mortality, and vaccine effectiveness

The MBL2 genotype relates to COVID-19 severity and may help to select the optimal therapy

Unraveling the impact of SARS-CoV-2 mutations on immunity: insights from innate immune recognition to antibody and T cell responses

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