Antibiotics help control rotavirus infections and enhance antirotaviral immunity: are you serious?

Yes and no. Yes, we must understand intriguing new findings; but no, we are far from serious about widespread use of antimicrobials with routine immunizations. In this issue, Uchiyama and colleagues [1] pry open our thinking about resident microbiota and host resistance to enteric viral infections. They describe how antibiotics (ampicillin and neomycin, given for 2–8 weeks) reduce murine rotavirus infections and symptoms and enhance rotavirus-specific immunoglobulin (Ig)A responses, effects that are partially mimicked in germ-free mice. Furthermore, they show that mild experimental dextran sulfate sodium (DSS) colitis (as reflected by increased fecal lipocalin-2, perhaps reflecting “enteropathy” seen in developing areas where enteric vaccine responses are impaired) impairs late ( perhaps acquired) fecal and serum IgA responses to rotavirus infections. As heretical as the use of antibiotics to ameliorate viral infections sounds, it is not without precedent. As the authors note, Kuss et al [2] previously showed that gut bacterial lipopolysaccharide (LPS) (or Bacillus cereus, peptidoglycan, or N-acetylglucosamine [GlcNAc]-containing polysaccharides) can bind to poliovirus or reovirus to facilitate their uptake and infectivity in the intestinal tract. Kuss et al [2] used human Poliovirus receptor (PVR)-transgenic interferon alpha/beta receptor–inactivated (PVRtg-Ifnar1) poliovirus-susceptible mice and HeLa cells to show that antibiotics reduce the infectivity of poliovirus as well as that of the unrelated enteric virus, reovirus (ie, increased susceptibility to enteric (rather than parenteral or intraperitoneal) poliovirus infection without antibiotics, and increased viability of poliovirus incubated in feces of germ-free mice supplemented with bacteria (B. cereus, Escherichia coli, or Enterococcus faecalis) or microbial surface products (LPS, peptidoglycan, mucin, chitin, or GlcNAc-containing polysaccharide)). Uchiyama’s finding of unchanged + : – rotavirus strand ratios suggests that viral entry, not intracellular viral replication, is altered by antibiotic treatment. Although other explanations such as the direct antiviral activity of thiazolides, for example, nitazoxanide have recently been offered [3], might Uchiyama’s findings that antibiotics can reduce viral infectivity through alteration of the resident microbiota further explain the perplexing benefit of nitazoxanide for rotavirus infections [4, 5]? Might these intriguing new concepts of viral pathogenesis also shed light on the differential benefit of adding probiotics (Saccharomyces boulardii alone or in combination with Lactobacillus acidophilus, Lactobacillus rhamnosus, and Bifidobacterium longum) to oral rehydration solutions (ORSs) for children with rotavirus compared with ORS monotherapy [6]? Similarly, how do interactions between resident flora and other select nonbacterial enteropathogens, including parasites and viruses, influence pathogenesis? Hayes et al, for example, have shown that intestinal microbes can induce the hatching of intestinal nematode eggs (Trichuris muris) in mice [7]. However, these heretical thoughts that imply antibiotics could help rotavirus diarrhea, control outbreaks, or even improve vaccine responses fly in the face of our conventional wisdom that antibiotic-mediated depletion of resident microbiota enhances susceptibility to some infections and that the overuse of antibiotics is driving increasingly worrisome drug resistance. Resident microbiota are needed for normal gut-associated lymphoid tissue development, drive T-cell and B-cell as well as dendritic cell and macrophage responses to influenza and lymhpocytic choriomeningitis (LCM) virus infections [8, 9] (References 11 and 12 within Uchiyama [1]), and have an obvious protective role in preventing such Received 25 February 2014; accepted 26 February 2014; electronically published 12 March 2014. Correspondence: Richard L. Guerrant, University of Virginia Center for Global Health, Charlottesville, VA 22908 (rlg9a@ virginia.edu). The Journal of Infectious Diseases 2014;210:167–70 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu153