Single nucleotide variant at the alphaVbeta3 integrin associated to Andes virus infection susceptibility.

Abstract

22 23 24 25 2 26 Abstract 27 Background: ANDV, agent of hantavirus cardiopulmonary syndrome, enters through 28 integrin cell protein. A change from leucine-to-proline at residues 33 in the PSI-domain 29 (L33P) inhibits ANDV recognition. We assessed the association between this human-30 variant and ANDV infection.31 Results: We defined susceptible genotype to "TT" (coding leucine) and protective "CC" 32 (coding proline). TT was in 89.2% (66/74) of a first cohort of ANDV-cases and in 60% 33 (63/105) of exposed close-household contacts who remained unifected (p<0.05).34 Protective genotype was absent in all 85 ANDV cases in both cohorts and was present at 35 11.4% in exposed close-household contacts who remained uninfected. Logistic regression 36 modeling to become a case had an OR 6.2-12.6 (p<0.05) in presence of TT and ANDV 37 well-known risk activities. Moreover, OR of 7.3 was obtained when TT condition was 38 analyzed for two groups exposed to the same environmental risk. 39 Conclusion: Host genetic background has an important role in ANDV-infection 40 susceptibility in the studied population.41 42 43 44 45 46 47 48 49 50 3 51 Author summary 52 Hantavirus is a worldwide infection known to cause two different diseases: the 53 hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary 54 syndrome (HCPS or HPS), diseases seen in the old world and new world hantaviruses, 55 respectively. Andes orthohantavirus (ANDV), is the etiological agent of HCPS in Chile 56 and South of Argentina, and is the only hantavirus recognized to be transmited person-57 to-person. It has been suggested that 3-integrin is a cellular receptor for ANDV entry 58 into cells. Here we try to understand the role of one human genetic variant of 3-integrin 59 in susceptibility to ANDV-infection. We compared, exposed infected and non infected 60 subjects, and their genotype differences regarding a 3 integrin variant that change a 61 Leucine to Proline at PSI domain of the receptor. Leucine and proline aminoacids at the 62 PSI domain, turn the cell susceptible or resistant to ANDV-infection, respectively. We 63 were able to show genotype differences in cases and close-household contact that suggest 64 differences in ANDV-infection susceptibility. Our results propose that the TT genotype, 65 that codes to leucine, is a risk factor to become infected with ANDV, and the CC genotype 66 that codes for proline at PSI domain, is a protective factor. (193/200) 67 68 69 70 71 72 73 74 75 100 (ECMO). Strikingly, some patients exhibit a mild disease with only minimal or total 101 absence of oxygen supplement requirement (10,11). 102Although risk factors for environmental and person-to-person transmission are 103 well characterized, host factors that determine susceptibility to infection and disease 104 severity are incompletely understood. In humans, pathogenic hantavirus such as ANDV 105 replicate primarily in vascular endothelial cells. As such, differences in virus-cell 106 affinity or the ability to attach to a known receptor may explai...