Genes May Determine Susceptibility to H5N1 Avian Influenza A Virus Infection
A new study found genetic variations in mice affect their susceptibility to and severity of H5N1 avian influenza A virus infection suggesting that humans who contract the virus may be genetically predisposed. The researchers from St. Jude Children's Research Hospital, VA Medical Center and MidSouth Center for Biodefense and Security, and the University of Tennessee Health Science Center, Memphis, Tennessee report their findings in the October 2009 issue of the Journal of Virology.
Over the last 10 years, highly pathogenic H5N1 avian influenza A has spread from Southeast Asia into Europe and Africa killing millions of chickens and ducks along the way. It has also infected tigers, cats, dogs and humans often resulting in death. Despite the countless cases reported in birds, the number of human cases remains few and of those few more than 90% occurred in genetically related family members indicating a possible genetic correlation.
In the study researchers conducted genome-wide linkage analysis to identify chromosomes that contribute to varying susceptibility to H5N1 in two inbred strains of mice challenged with a lethal dose of a highly pathogenic H5N1 virus. Results revealed five quantitative trait loci for influenza virus resistance located on multiple chromosomes also associated with H5N1 resistance. Additionally, a number of candidate susceptibility genes were identified, one of which affected virus titers 7 days following infection.
"An important and novel finding of this study is that H5N1-induced pathology is greatly affected by genetic polymorphisms in the genome of the infected host," say the researchers. "We have also found that, at least in mice, H5N1 pathogenesis is a complex genetic trait with multiple genes affecting disease outcome."
(A.C.M. Boon, J. deBeauchamp, A. Hollmann, J. Luke, M. Kotb, S. Rowe, D. Finkelstein, G. Neale, L. Lu, R.W. Williams, R.J. Webby. 2009. Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice. Journal of Virology, 83. 20: 10417-10426.)
Cigarette Smoke May Impair Lungs Natural Defense Against Harmful Pathogen
Exposure to cigarette smoke may impair the ability of immune cells to clear bacterial infections from the lungs, specifically nontypeable Haemophilus influenzae (NTHI), a pathogen often associated with respiratory infections and the progression of respiratory diseases. The researchers from Spain and the United Kingdom report their findings in the October 2009 issue of the journal Infection and Immunity.
NTHI, commonly found in the human respiratory tract, may remain asymptomatic in healthy individuals or it can cause invasive diseases such as meningitis, sinusitis, pneumonia, and bronchitis. It is also the pathogen most frequently isolated in the respiratory tract of patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis. Alveolar macrophages are part of the lungs' innate defense system and they play an essential role in the clearance of bacterial infections. Prior associations between cigarette smoke and respiratory infections caused by NTHI have been established and now researchers are hypothesizing that cigarette smoke may disrupt the capability of alveolar macrophages to clear NTHI from the lungs.
In the study researchers first examined the interaction between NTHI and alveolar macrophages and found that the macrophages adhere to and ingest NTHI, a process known as phagocytosis. Researchers also observed the effect of cigarette smoke in macrophage cell lines and human alveolar macrophages obtained from smokers and patients with COPD and found that cigarette smoke extract impaired the alveolar macrophage process. Additionally, cells exposed to cigarette smoke extract were treated with glucocorticoid, an anti-inflammatory drug commonly used to treat respiratory conditions, and results showed that the drug did not compensate for the impairment to the alveolar macrophage process caused by the cigarette smoke.
"This study revealed novel effects of cigarette smoking on alveolar macrophage physiological functions which could contribute to lung bacterial colonization by opportunistic pathogens, such as NTHI," say the researchers.
(P. Marti-Lliteras, V. Regueiro, P. Morey, D.W. Hood, C. Saus, J. Sauleda, A.G.N. Agusti, J.A. Bengoechea, J. Garmendia. 2009. Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke. Infection and Immunity, 77. 10: 4232-4242.)
T-Cell Vaccine Reduces Simian Immunodeficiency Virus Levels in Semen of Monkeys During Primary Infection
A new study reports that a vaccine-induced cellular immune response reduced simian immunodeficiency virus (SIV) levels in the semen of rhesus monkeys during the period of primary infection, a discovery that may ultimately aid in the fight against HIV-1 transmission in humans. The researchers from Harvard Medical School, Boston, Massachussetts; Los Alamos National Laboratory, Los Alamos, New Mexico; and the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland detail their findings in the October 2009 issue of the Journal of Virology.
HIV-1 replication peaks during the period of primary infection, therefore it is estimated that 50% of sexually contracted HIV-1 cases occur when the individual transmitting the virus is newly infected. No vaccines capable of inducing antibodies that completely neutralize a variety of HIV-1 isolates are currently available, however prior studies show that vaccine-elicited, virus-specific T-lymphocyte populations can limit viral replication during primary infection in nonhuman primates.
In the study two groups of rhesus monkeys were immunized with either vaccine vectors expressing SIV Gag/Pol or control vaccine constructs following which both were challenged intravenously with a highly pathogenic SIV quasispecies. Semen samples were collected from both groups of monkeys once a week for six weeks and then bi-weekly up to 16 weeks to evaluate both the acute and set point phase of SIV viremia. Analysis of the collected semen samples showed that SIV RNA was detected by day 7 in the control group and reached a peak at day 28 postinfection, while in the Gag/Pol group SIV RNA wasn't detected until day 14, reached a peak at day 21, declined to undetectable levels by day 42 postinfection and remained that way for the duration of the study. Significantly, the peak virus RNA level in the semen of the Gag/Pol group was found to be lower than the control group and it remained substantially lower from days 28 to 80 postinfection.
"The demonstration in the present study of a direct association between vaccination and diminished seminal plasma SIV RNA levels suggests that vaccination may be an effective measure for reducing HIV-1 transmission," say the researchers.
(J.B. Whitney, C. Luedemann, P. Hraber, S.S. Rao, J.R. Mascola, G.J. Nabel, N.L. Letvin. 2009. T-cell vaccination reduces simian immunodeficiency virus levels in semen. Journal of Virology, 83. 20: 10840-10843.)
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