Why some individuals resist infection or recover quickly, whereas others experience severe disease associated with infection, is a fundamental question that medicine has struggled to answer. Pathogens and host immune factors have been extensively investigated for many infectious diseases, to address these questions. However, limited information is available concerning the influence of host genetics on the response to viral infections. Genetic determinants have the potential to play a role at numerous points during the course of viral infection, including viral attachment and entry, replication, disease progression and development of severity, and, finally, transmission. In this issue of the Journal, Albright et al. [1] propose that the severity of influenza illness may have a heritable component. To investigate this hypothesis, the authors used as a resource the Utah Population Data Base, which contains data from founding families and their descendants, comprised primarily of members of the Church of Jesus Christ of Latter-Day Saints (i.e., Mormons), thus representing a relatively ethnically homogeneous population. Albright et al. [1] estimated the relative risk (RR) of death for relatives of 4855 individuals (spanning 3 generations) who died of influenza. A substantial proportion of deaths occurred during the 1918 influenza pandemic, when a total of 1937 deaths were documented between 1918 and 1921, and 1293 additional deaths occurred between 1922–1932, followed by a dramatic decrease in the number of deaths occurring annually. The RR of death for first-degree relatives was 1.54 (P .0001). The RR was higher for spouses (1.98) and for secondand third-degree relatives (1.22 and 1.16, respectively). The timing of the deaths of third-degree relatives suggests that the deaths were not the result of a common exposure. To control for shared environment, the RR of death for spouses’ relatives was compared and was found to be lower for first-, second-, and third-degree relatives. Excess relatedness among individuals dying of influenza was estimated using the Geneological Index of Familiality, which demonstrated that relatedness among these individuals, including individuals who died during the 1918 pandemic, was greater than expected (P .001). The analysis was repeated with close relatives excluded (to control for shared environment), and the results were consistent with previous findings. Consistent results were not observed when the same analysis was repeated for individuals with diphtheria-associated deaths. For such individuals, excess relatedness was demonstrated; however, when close relationships were excluded, no excess relatedness was detected. Specific genes responsible for the host immune response have been invoked as major determinants of the clinical course of HIV-associated disease and hepatitis B and C virus infections [2, 3]. However, there is very little information with respect to genetic determinants as they relate to severe influenza. Over the past decade, a greater understanding of the immune evasion strategies of influenza virus has developed. This knowledge can be used to propose several candidate genes that may be responsible for severe illness. Clinical and animal studies indicate that cytokine dysregulation is associated with acute respiratory distress syndrome and death among hosts infected with avian influenza virus (H5N1) [4 – 6]. Toll-like receptors (TLRs), particularly TLR3 (which recognizes double-stranded RNA) and TLR7 and TLR8 (which recognize single-stranded RNA), are central to antiviral innate immunity [7]. Singlenucleotide polymorphisms in TLR genes are not uncommon and vary among populations [8]. TLR4 has been implicated in the innate immune response to respiratory syncytial virus (RSV) infection, and polymorphisms in the TLR4 gene have Received 5 July 2007; accepted 5 July 2007; electronically published 7 December 2007. Potential conflicts of interest: none reported. Financial support: W. M. Keck Foundation (to P.P.); National Institutes of Health (grant P01 AI158113 to P.P.); Northeast Biodefense Center (grant U54 AI057158 to P.P.); Center for Investigating Viral Immunity and Antagonism (grants U19 AI62623 and U01 CI 000354 [R21 to P.P.]); Ruth L. Kirschstein Physician Scientist Research Training in Pathogenesis of Viral Diseases Award (to S.M.); Sunnybrook Health Sciences Centre, University of Toronto, Canada (salary support to S.M.). Reprints or correspondence: Dr. Samira Mubareka, Dept. of Microbiology, Mount Sinai School of Medicine, 1 Gustave Levy Pl., Box 1124, New York, NY 10029 (samira.mubareka@mssm.edu). The Journal of Infectious Diseases 2008; 197:1–3 © 2007 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19701-0001$15.00 DOI: 10.1086/524067 E D I T O R I A L C O M M E N T A R Y