Sendai virus intra-host population dynamics and host immunocompetence influence viral virulence during in vivo passage

Peña, José; Chen-Harris, Haiyin; Allen, Jonathan E.; Hwang, Mona; Elsheikh, Maher; Mabery, Shalini; Bielefeldt-Ohmann, Helle; Zemla, Adam T.; Bowen, Richard A.; Borucki, Monica K.

Host nutritional status may influence the generation of variant viruses and thus the viral genotype by a number of mechanisms. Both selenium and vitamin E are antioxidants and function to control oxidative stress that is induced as part of the host response to infection. Although production of reactive oxygen species such as nitric oxide may play a role in microbial clearance, it may also act as a mutagen and therefore may expand the diversity of the mutant spectra by acting on the fidelity of the viral polymerases (Domingo 1997; Akaike et al. 2000) . The effect of oxidative stress on viral evolution has been demonstrated in a variety of viruses (influenza, coxsackie, polio, Sendai, and human immunodeficiency virus) and hosts (mouse, human) (Akaike et al. 2000; Beck et al. 2001; Beck, Williams-Toone, and Levander 2003; Beck, Handy, and Levander 2004) . Selenium deficiency has also been shown to impair the cellular and humoral immune response. Similarly, obesity leads to increased oxidative stress and immune dysregulation although through a different mechanism driven by chronic inflammation (Monteiro and Azevedo 2010; Kanneganti and Dixit 2012; Aroor and DeMarco 2014) . In particular, obesity has been shown to reduce cytokine production and NK cell cytotoxicity (Akaike et al. 2000; Beck et al. 2001; Beck, Williams-Toone, and Levander 2003; Beck, Handy, and Levander 2004; Smith et al. 2007 ). The presence of excess dietary iron, which has a pro-oxidant effect in vivo, may also increase viral titer and virulence (Beck, Handy, and Levander 2004) .