Understanding the Flu: Host and Environmental Factors Associated With Susceptibility to Influenza Virus-Induced Disease

Discussion

In this paper, we reviewed current experimental and epidemiological evidence for host and environmental factors associated with influenza virus susceptibility. Although recent studies have attempted to associate specific genes and genetic polymorphisms with influenza virus susceptibility or resistance, most of the available data for susceptibility factors involves activation of the immune response in the infected host according to genetic predisposition or exposure to various environmental stimuli. The current lack of identified influenza susceptibility genes is likely attributed to the difficulties associated with invasive research in human population-based association studies. Animal models, such as the mouse, ferret, cotton rat, hamster and macaque, have been a useful way to study influenza virus pathogenesis, and mice in particular have enabled the identification of several candidate susceptibility genes. Other factors, such as gender and preexisting medical conditions, have also been associated with complications resulting from influenza virus infection (83,160,161).

On the other hand, many aspects of the field remain unresolved because of contradictory reports in the literature and a lack of human-based research studies. Despite extensive research examining the effects of influenza virus infection and/or vaccination in pregnant and immunosenescent individuals, for example, conflicting reports still remain on the risk of fetal congenital anomalies to infected pregnant women and the efficacy of influenza vaccination in the aged population. Although multiple studies have demonstrated an association between influenza-associated complications and preexisting medical conditions such as asthma and COPD, few studies have demonstrated a causal relationship between exacerbations of these respiratory conditions and influenza virus infection. Moreover, studies utilizing mouse models of influenza virus infection have identified several genetic factors that are implicated in influenza virus susceptibility; however, many of these genetic associations have not yet been validated by human studies.

A significant amount of the research that has focused on the effects of stress on the host, either physical or emotional, shows that stress causes increased morbidity and mortality following influenza virus infection. In murine studies, inflammation caused by stress appears to play a critical role in this increased susceptibility. Host nutritional status is also an important factor in determining susceptibility to and outcome of influenza virus infection. Not surprisingly, the ability to mount a sufficient immune response against the virus was diminished in mice deprived of essential vitamins and nutrients. Interestingly, polyunsaturated fatty acids such as fish oil, which have gained popularity in recent years for their anti-inflammatory properties, had an adverse effect on the clearance and recovery from influenza virus infection in mice. The protective effect of polyunsaturated fats during influenza virus infection has yet to be studied in humans; however, given their widespread use, epidemiologic studies are warranted. In addition to undernutrition, obesity also affects the severity of influenza-induced disease and was identified as a major risk factor for hospitalization and death during the 2009 H1N1 pandemic.

It is well known that cigarette smoke (firsthand and secondhand) and other environmental pollutants puts those exposed at higher risk for more severe respiratory infections, and studies of influenza infections in humans and animal models corroborate that concept. One exception is studies looking at exposure to ozone, which has been shown to both increase and decrease severity of influenza virus pathogenesis in mice depending on the dose and duration of exposure. Further studies are needed to clarify the role of ozone exposure in the host immune response to influenza virus infection. The effect of alcohol exposure on influenza virus infection has only been studied in mice. While these studies show that both chronic and fetal alcohol exposure increases susceptibility to viral infection, observational epidemiologic studies would be worthwhile to determine if alcohol consumption affects the severity of influenza-induced disease in humans.

Despite significant advances in the identification of host susceptibility factors for influenza virus pathogenesis, there remains significant defects in the verification of these factors in humans. Innate differences between human and animal models of influenza virus disease present difficulties in determining whether candidate susceptibility factors in animals will carry over to the human infection, and the invasive experiments that are performed in animals cannot be practically or safely applied to humans. More extensive research involving human-based studies, including population-based approaches involving large cohorts from multiple geographic locations, will be necessary to augment the current state of knowledge in the influenza field and allow for the identification (or validation) of specific environmental and genetic risk factors associated with influenza-induced disease.

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Table 1: Studies of host and environmental factors associated with susceptibility to influenza virus infection, by study type.

Host/environmental risk factor	Epidemiologic studies	Animal model studies	In vitro studies
Genetics	14-21	22-31
Immunity -Natural immunity -Immunosenescence	42 55, 56	32-40, 43-47, 49-53 57	47, 48
Pregnancy	60-69
Chronic Respiratory Conditions	70-78
Stress -Family functioning -Restraint stress -Exercise stress -Stress early in life -Psychosocial stress	79	80-83 84, 85 86-90 91
Nutrition -Protein-energy deficiencies -Obesity -Vitamin and micronutrient deficiencies	107*, 108	104-105, 108-109 110, 111 93, 98, 111, 113-114, 120-123
Smoking	125-129	131	130, 132
Alcohol		136-138
Pollutants -General -Diesel exhaust -Ozone -2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)	140-144 146	148-150 153-156 158-159	147

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Acknowledgements

This work was supported by the DoD-funded National Defense Science and Engineering Graduate (NDSEG) Fellowship awarded to Lauren M. Neighbours. We thank Bill Saunders and Chris Blanchette for their critical analysis of the manuscript and helpful comments.