In Vivo Models to Study the Pathogenesis of Extra-Respiratory Complications of Influenza A Virus Infection

Abstract

Animal models are an inimitable method to study the systemic pathogenesis of virus-induced disease. Extra-respiratory complications of influenza A virus infections are not extensively studied even though they are often associated with severe disease and mortality. Here we review and recommend mammalian animal models that can be used to study extra-respiratory complications of the central nervous system and cardiovascular system as well as involvement of the eye, placenta, fetus, lacteal gland, liver, pancreas, intestinal tract, and lymphoid tissues during influenza A virus infections.

Keywords: cardiovascular disease; central nervous system disease; cranial nerves; extra-respiratory disease; influenza; mammalian animal models; olfactory nerve; pathogenesis.

Figure 1

Influenza viral antigen in different organs and animal models. (A) HPAI H5N1 virus in the olfactory bulb of intranasal inoculated ferrets. Viral antigen is detected in cells surrounding the glomeruli. (B) HPAI H5N1 virus in the cerebrum of an intranasal inoculated ferret. Viral antigen is detected predominantly in neurons (adapted from Schrauwen et al. [15]). (C) HPAI H5N1 virus in the heart of a H5N1 intratracheal inoculated cat (adapted from Rimmelzwaan et al., 2006 [47]). Viral antigen is detected in cardiac myocytes. (D) 1918 H1N1 virus in the liver of an intranasal inoculated ferret. Viral antigen is detected in hepatocytes (adapted from Figure 5 of de Wit et al. [24], reproduced by permission of Oxford University Press).

Figure 2

Animal models to study different extra-respiratory complication. Circles depict organs in which influenza A viruses have been detected, and which are discussed in the review. In the zoom out, established experimental animal species to study extra-respiratory spread of each organ are represented. In black are the animal models that have been used and described most extensively.