viruses Review Role of the Host Genetic Susceptibility to 2009 Pandemic Influenza A H1N1 Gloria Pérez-Rubio 1,† , Marco Antonio Ponce-Gallegos 1,† , Bruno André Domínguez-Mazzocco 1, Jaime Ponce-Gallegos 2, Román Alejandro García-Ramírez 1 and Ramcés Falfán-Valencia 1,* 1 HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico; [email protected] (G.P.-R.); [email protected] (M.A.P.-G.); [email protected] (B.A.D.-M.); [email protected] (R.A.G.-R.) 2 High Speciality Cardiology Unit “Korazón”, Puerta de Hierro Hospital, Tepic 63173, Nayarit, Mexico; [email protected] * Correspondence: [email protected]; Tel.: +52-55-5487-1700 (ext. 5152) † These authors contributed equally to this work. Abstract: Influenza A virus (IAV) is the most common infectious agent in humans, and infects approximately 10–20% of the world’s population, resulting in 3–5 million hospitalizations per year. A scientific literature search was performed using the PubMed database and the Medical Subject Head- ings (MeSH) “Influenza A H1N1” and “Genetic susceptibility”. Due to the amount of information and evidence about genetic susceptibility generated from the studies carried out in the last influenza A H1N1 pandemic, studies published between January 2009 to May 2020 were considered; 119 papers were found. Several pathways are involved in the host defense against IAV infection (innate immune Citation: Pérez-Rubio, G.; response, pro-inflammatory cytokines, chemokines, complement activation, and HLA molecules Ponce-Gallegos, M.A.; participating in viral antigen presentation). On the other hand, single nucleotide polymorphisms Domínguez-Mazzocco, B.A.; (SNPs) are a type of variation involving the change of a single base pair that can mean that encoded Ponce-Gallegos, J.; García-Ramírez, proteins do not carry out their functions properly, allowing higher viral replication and abnormal host R.A.; Falfán-Valencia, R. Role of the response to infection, such as a cytokine storm. Some of the most studied SNPs associated with IAV Host Genetic Susceptibility to 2009 infection genetic susceptibility are located in the FCGR2A, C1QBP, CD55, and RPAIN genes, affecting Pandemic Influenza A H1N1. Viruses 2021, 13, 344. https://doi.org/ host immune responses through abnormal complement activation. Also, SNPs in IFITM3 (which 10.3390/v13020344 participates in endosomes and lysosomes fusion) represent some of the most critical polymorphisms associated with IAV infection, suggesting an ineffective virus clearance. Regarding inflammatory Academic Editors: Angela response genes, single nucleotide variants in IL1B, TNF, LTA IL17A, IL8, IL6, IRAK2, PIK3CG, and L. Rasmussen and Juliet Morrison HLA complex are associated with altered phenotype in pro-inflammatory molecules, participating in IAV infection and the severest form of the disease. Received: 23 December 2020 Accepted: 18 February 2021 Keywords: influenza; inflammation; genetic susceptibility; polymorphisms; cytokine storm Published: 22 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- Orthomyx- iations. Influenza A virus (IAV), a single-stranded negative-sense RNA virus of the oviridae family, is the most common infectious agent in humans, causing significant mor- bidity and mortality in infants and the elderly every year [1,2]. Also, influenza infects approximately 10–20% of the world’s population resulting in 3–5 million hospitalizations each year and an estimated 87.1 billion dollars in total annual economic burden in the Copyright: © 2021 by the authors. United States alone [3]. Since 1918, humankind has experienced three influenza pandemics: Licensee MDPI, Basel, Switzerland. the “Asian” influenza pandemic, in 1957, the “Hong Kong” influenza pandemic in 1968, This article is an open access article and the 2009 so-named “swine flu” pandemic. Although mild compared to that of 1918, distributed under the terms and conditions of the Creative Commons these pandemics highlight the constant threat that the influenza virus poses to human Attribution (CC BY) license (https:// health [4]. creativecommons.org/licenses/by/ In April 2009, the first influenza A H1N1 cases were registered in Mexico and as- 4.0/). sociated with a surprising number of deaths [5], and it spread rapidly throughout the Viruses 2021, 13, 344. https://doi.org/10.3390/v13020344 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 344 2 of 21 world [6]. Worldwide, estimates of the crude hospitalization fatality risk (HFR), defined as the probability of death among H1N1 pdm09 cases which required hospitalization for medical reasons, ranged from 0% to 52%, with higher estimates from tertiary-care referral hospitals in countries with a lower gross domestic product. However, in wealthy countries, the estimation was 1%–3% in all settings [7]. 2. Bibliometric Analysis A scientific literature search was performed using the PubMed database; the Medical Subject Headings (MeSH) “Influenza A H1N1” AND “Genetic susceptibility” were used. Studies published between January 2009 to May 2020 were included due to the amount of information and evidence about genetic susceptibility generated from the studies carried out in the last influenza A H1N1 pandemic. The bibliometric analysis was performed using RISmed [8], and for the wordcloud creation with the keywords of articles included in this review, we used the wordcloud tool [9] in RStudio V 3.6.1 [10] following the workflow proposed by the libraries developer. Applying this criteria selection, 119 papers were identified. Figure1 shows articles published with these MeSH by year in the period, as mentioned above, and journals where papers were published. Figure 1. (a) Publications with the words “influenza A H1N1” and “genetic susceptibility” published between January 2009 to May 2020. (b) Top 25 journals where the 119 articles were published. A wordcloud showing the main keywords terms in the bibliometric analysis is shown in Figure2. Viruses 2021, 13, 344 3 of 21 Figure 2. Depicting word cloud showing main keywords in the bibliometric analysis. 3. Inflammatory Response and IFITM3 Role in Influenza A Virus Infection Through experimental and clinical studies, the systemic inflammatory dysregulation correlating with the disease’s severity and progression has been identified as one of the most important pathogenic mechanisms in infection [11,12]. Cytokine secretion by infected cells is necessary for the initiation of the immune response that controls virus replication [13]; also, immunopathological mechanisms such as hypercytokinemia (also known as cytokine storm) generally contribute to the more severe evolution of the infection [14,15]. A cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined [16]. Critically ill patients who de- veloped ARDS related to influenza A H1N1 virus infection had a slower decline in na- sopharyngeal viral loads; had higher plasma levels of pro-inflammatory cytokines and chemokines; and were more likely to have bacterial coinfections, myocarditis, or viremia than patients in the survived-without-ARDS or the mild-disease groups. The hallmarks of the severity of disease were interleukin-(IL)-6, IL-8 and Tumor necrosis factor (TNF)-α [17]. The genes encoding these proteins are polymorphic, and specific alleles have been associ- ated with susceptibility to different diseases, covering a broad spectrum of pathologies, from infectious to oncological, including pulmonary and systemic diseases [18–20]. These genes’ extensive polymorphism could be associated with the high mortality rate during the A H1N1 influenza pandemic in Mexico and its high prevalence. According to Borja et al. 2012, a fourth wave observed in Mexico during 2011–2012 was not reported in other countries. Therefore, these differences could be explained by patterns of genetic susceptibility in Mexicans or vaccination coverage failures [21]. Elevated serum levels of IL-1β and IL-6 have been identified as markers of severity in acute lung damage during influenza A H1N1 virus pdm09 infection; additionally, elevated levels of IL-1β are considered an early biomarker of the severity and progression of lung inflammation in patients who require mechanical ventilation and who do not respond to conventional antimicrobial treatments [22,23]. For example, the UK experienced two waves, one in spring–autumn 2009, followed by a more severe one in 2010–2011 [24,25], which was not seen in other European countries. These differences could be explained by geographic variations, previous immunity, control strategies, connectivity, public health, and for now, it remains a key for future research. The defense mechanism that is provided by the innate immune system is the quintessen- tial barrier, a specialized immune system in which different mucosa co-exist that fights the invasion of pathogens. The viral RNA is recognized as foreign by the different Pattern Viruses 2021, 13, 344 4 of 21 Recognition Receptors (PRRs) present in infected cells, which secrete type I interferons (IFNs), pro-inflammatory cytokines, eicosanoids, and chemokines [26]. Type I interfer- ons, produced by macrophages, pneumocytes, dendritic cells, and plasmacytoid dendritic cells (pDCs), stimulate the expression of hundreds of collectively called IFN-stimulating genes (ISGs) in neighboring cells, which induce an antiviral state. Pro-inflammatory cy- tokines