Samira Mubareka

Bio: Samira Mubareka is an academic researcher from Icahn School of Medicine at Mount Sinai. The author has contributed to research in topics: Influenza A virus & Virus. The author has an hindex of 5, co-authored 5 publications receiving 2229 citations.

Influenza virus transmission is dependent on relative humidity and temperature.

Abstract: Using the guinea pig as a model host, we show that aerosol spread of influenza virus is dependent upon both ambient relative humidity and temperature. Twenty experiments performed at relative humidities from 20% to 80% and 5 °C, 20 °C, or 30 °C indicated that both cold and dry conditions favor transmission. The relationship between transmission via aerosols and relative humidity at 20 °C is similar to that previously reported for the stability of influenza viruses (except at high relative humidity, 80%), implying that the effects of humidity act largely at the level of the virus particle. For infected guinea pigs housed at 5 °C, the duration of peak shedding was approximately 40 h longer than that of animals housed at 20 °C; this increased shedding likely accounts for the enhanced transmission seen at 5 °C. To investigate the mechanism permitting prolonged viral growth, expression levels in the upper respiratory tract of several innate immune mediators were determined. Innate responses proved to be comparable between animals housed at 5 °C and 20 °C, suggesting that cold temperature (5 °C) does not impair the innate immune response in this system. Although the seasonal epidemiology of influenza is well characterized, the underlying reasons for predominant wintertime spread are not clear. We provide direct, experimental evidence to support the role of weather conditions in the dynamics of influenza and thereby address a long-standing question fundamental to the understanding of influenza epidemiology and evolution.

Transmission of Influenza Virus in a Mammalian Host Is Increased by PB2 Amino Acids 627K or 627E/701N

Abstract: Since 2003, more than 380 cases of H5N1 influenza virus infection of humans have been reported. Although the resultant disease in these cases was often severe or fatal, transmission of avian influenza viruses between humans is rare. The precise nature of the barrier blocking human-to-human spread is unknown. It is clear, however, that efficient human-to-human transmission of an antigenically novel influenza virus would result in a pandemic. Influenza viruses with changes at amino acids 627 or 701 of the PB2 protein have been isolated from human cases of highly pathogenic H5 and H7 avian influenza. Herein, we have used the guinea pig model to test the contributions of PB2 627 and 701 to mammalian transmission. To this end, viruses carrying mutations at these positions were generated in the A/Panama/2007/99 (H3N2) and A/Viet Nam/1203/04 (H5N1) backgrounds. In the context of either rPan99 or rVN1203, mutation of lysine 627 to the avian consensus residue glutamic acid was found to decrease transmission. Introduction of an asparagine at position 701, in conjunction with the K627E mutation, resulted in a phenotype more similar to that of the parental strains, suggesting that this residue can compensate for the lack of 627K in terms of increasing transmission in mammals. Thus, our data show that PB2 amino acids 627 and 701 are determinants of mammalian inter-host transmission in diverse virus backgrounds.

The guinea pig as a transmission model for human influenza viruses

Abstract: The severity of epidemic and pandemic influenza outbreaks is dictated in part by the efficiency with which the causative strain transmits between human hosts. The mechanisms underlying influenza virus spread are poorly understood, in part because of the lack of a convenient animal model to study this phenomenon. Indeed, despite extremely efficient transmission among humans and virulence in the mouse model, we have shown that even the 1918 pandemic influenza virus does not transmit between mice. We therefore evaluated the guinea pig as a model mammalian host for influenza virus. Using the recent human isolate A/Panama/2007/99 (Pan/99) (H3N2) virus, we found that guinea pigs were highly susceptible to infection with the unadapted virus (ID50 = 5 plaque-forming units). Pan/99 virus grew to high titers in the upper respiratory tract and was shed in nasal washings of infected animals. Moreover, influenza virus was transmitted from infected guinea pigs to noninfected guinea pigs housed in the same cage, an adjacent cage, and a cage placed 91 cm away. Our results demonstrate that influenza virus can pass between guinea pigs by means of droplet spread and thereby establish the suitability of the guinea pig as a model host for influenza virus transmission studies.

Transmission of Influenza Virus via Aerosols and Fomites in the Guinea Pig Model

Abstract: Limited data on the relative contributions of different routes of transmission for influenza virus are available. Person-to-person transmission is central to seasonal and pandemic spread; nevertheless, the modes of spread are a matter of ongoing debate. Resolution of this discussion is paramount to the development of effective control measures in health care and community settings. Using the guinea pig model, we demonstrated that transmission of influenza A/Panama/2007/1999 (H3N2) virus through the air is efficient, compared with spread through contaminated environmental surfaces (fomites). We also examined the aerosol transmission efficiencies of 2 human influenza virus A strains and found that A/Panama/2007/1999 influenza virus transmitted more efficiently than A/Texas/36/1991 (H1N1) virus in our model. The data provide new and much-needed insights into the modes of influenza virus spread and strain-specific differences in the efficiency of transmission.

Human Genes and Influenza

Abstract: 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

Antigenic and Genetic Characteristics of Swine-Origin 2009 A(H1N1) Influenza Viruses Circulating in Humans

Abstract: Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North American and Eurasian swine lineages has continued to circulate in humans. The lack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period. Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses. Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1).

Emergence and pandemic potential of swine-origin H1N1 influenza virus.

Abstract: Influenza viruses cause annual epidemics and occasional pandemics that have claimed the lives of millions. The emergence of new strains will continue to pose challenges to public health and the scientific communities. A prime example is the recent emergence of swine-origin H1N1 viruses that have transmitted to and spread among humans, resulting in outbreaks internationally. Efforts to control these outbreaks and real-time monitoring of the evolution of this virus should provide us with invaluable information to direct infectious disease control programmes and to improve understanding of the factors that determine viral pathogenicity and/or transmissibility.

Airborne transmission of influenza A/H5N1 virus between ferrets

Abstract: Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far has not acquired the ability to be transmitted by aerosol or respiratory droplet ("airborne transmission") between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets. None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses. Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses. The transmissible viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. Thus, avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host and therefore constitute a risk for human pandemic influenza.

Influenza virus transmission is dependent on relative humidity and temperature.

Abstract: Using the guinea pig as a model host, we show that aerosol spread of influenza virus is dependent upon both ambient relative humidity and temperature. Twenty experiments performed at relative humidities from 20% to 80% and 5 °C, 20 °C, or 30 °C indicated that both cold and dry conditions favor transmission. The relationship between transmission via aerosols and relative humidity at 20 °C is similar to that previously reported for the stability of influenza viruses (except at high relative humidity, 80%), implying that the effects of humidity act largely at the level of the virus particle. For infected guinea pigs housed at 5 °C, the duration of peak shedding was approximately 40 h longer than that of animals housed at 20 °C; this increased shedding likely accounts for the enhanced transmission seen at 5 °C. To investigate the mechanism permitting prolonged viral growth, expression levels in the upper respiratory tract of several innate immune mediators were determined. Innate responses proved to be comparable between animals housed at 5 °C and 20 °C, suggesting that cold temperature (5 °C) does not impair the innate immune response in this system. Although the seasonal epidemiology of influenza is well characterized, the underlying reasons for predominant wintertime spread are not clear. We provide direct, experimental evidence to support the role of weather conditions in the dynamics of influenza and thereby address a long-standing question fundamental to the understanding of influenza epidemiology and evolution.

Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths.

Abstract: The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.