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The CCR5?32 allele is not a major predisposing factor for severe H1N1pdm09 infection.

ABSTRACT: BACKGROUND: Host genetic factors are thought to modulated the severity of disease caused by infection with the 2009 H1N1 pandemic influenza virus (H1N1pdm09). The human CCR5 gene encodes a cytokine receptor important for cell-mediated immune response against H1N1pdm09. A 32-bp polymorphic deletion in the coding sequence of CCR5, the so-called CCR5?32 allele, segregates in populations of European ancestry with a frequency of 8-15%. A high proportion of CCR5?32 heterozygotes was reported in a sample of white Canadian critically-ill H1N1pdm09 infected subjects, suggesting an association with disease severity. METHODS: We recruited 29 H1N1pdm09 infected subjects from Southern Europe (mostly Italians) with a wide clinical spectrum of disease symptoms; the sample included 7 subjects who developed acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. The CCR5?32 variant was genotyped in all subjects. RESULTS: The CCR5?32 allele was found in one single subject, who developed a very mild form and was not hospitalized. CONCLUSIONS: The CCR5?32 allele was not found to be associated with the risk of H1N1pdm09 infection or with a severe disease course.

SUBMITTER: Sironi M

PROVIDER: S-EPMC4132245 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The CCR5Δ32 allele is not a major predisposing factor for severe H1N1pdm09 infection.

Sironi Manuela M Cagliani Rachele R Pontremoli Chiara C Rossi Marianna M Migliorino Guglielmo G Clerici Mario M Gori Andrea A

BMC research notes 20140807

<h4>Background</h4>Host genetic factors are thought to modulated the severity of disease caused by infection with the 2009 H1N1 pandemic influenza virus (H1N1pdm09). The human CCR5 gene encodes a cytokine receptor important for cell-mediated immune response against H1N1pdm09. A 32-bp polymorphic deletion in the coding sequence of CCR5, the so-called CCR5Δ32 allele, segregates in populations of European ancestry with a frequency of 8-15%. A high proportion of CCR5Δ32 heterozygotes was reported in ...[more]

PMID: 25100510

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Project description:Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and currently has detrimental human health, community, and economic impacts around the world. It is unclear why some SARS-CoV-2-positive individuals remain asymptomatic, while others develop severe symptoms. Baseline pulmonary levels of antiviral leukocytes, already residing in the lung prior to infection, may orchestrate an effective early immune response and prevent severe symptoms. Here, "in silico flow cytometry" was used to deconvolute the levels of all seven types of antiviral leukocytes in 1,927 human lung tissues. Baseline levels of CD8+ T cells, resting NK cells, and activated NK cells, as well as cytokines that recruit these cells, are significantly lower in lung tissues with high expression of the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2). This is observed in univariate analyses, in multivariate analyses, and in two independent data sets. Importantly, ACE2 mRNA and protein levels very strongly correlate in human cells and tissues. The above findings also largely apply to the SARS-CoV-2 entry protease TMPRSS2. Both SARS-CoV-2-infected lung cells and COVID-19 lung tissues show upregulation of CD8+ T cell- and NK cell-recruiting cytokines. Moreover, tissue-resident CD8+ T cells and inflammatory NK cells are significantly more abundant in bronchoalveolar lavage fluids from mildly affected COVID-19 patients compared to severe cases. This suggests that these lymphocytes are important for preventing severe symptoms. Elevated ACE2 expression increases sensitivity to coronavirus infection. Thus, the results suggest that some individuals may be exceedingly susceptible to develop severe COVID-19 due to concomitant high preexisting ACE2 and TMPRSS expression and low baseline cytotoxic lymphocyte levels in the lung.IMPORTANCE COVID-19 is caused by the highly contagious coronavirus SARS-CoV-2 and currently has detrimental human health, community, and economic impacts around the world. It is unclear why some SARS-CoV-2-positive individuals develop severe COVID-19 symptoms, which can be fatal, while others only develop mild symptoms. In the absence of an effective and widely available vaccine, it is of paramount importance that we identify risk factors for development of severe symptoms to be able to improve treatment approaches. The ACE2 gene encodes the receptor on human cells that the virus uses to infect these cells. This study finds that if the lungs of healthy individuals have high levels of ACE2, they typically have low levels of the immune cells that eliminate viruses. Therefore, some individuals may develop severe COVID-19 due to simultaneous high levels of the virus receptor and low levels of immune cells that eradicate the virus in their lungs.

Project description:The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human C-C chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed.

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The CCR5?32 allele is not a major predisposing factor for severe H1N1pdm09 infection.

Publications

The CCR5Δ32 allele is not a major predisposing factor for severe H1N1pdm09 infection.

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