Van Reeth K. Cytokines in the pathogenesis of influenza. Vet Microbiol. 2000 May 22;74(1-2):109-16. PMID: 10799783

Uncomplicated influenza in humans, horses or swine is characterized by massive virus replication in respiratory epithelial cells, inflammation and an abrupt onset of general and respiratory disease. There is now growing evidence that the so-called early cytokines produced at the site of infection mediate many of the clinical and pathological manifestations. Among these cytokines are interferon-alpha (IFN-alpha), tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) alpha and beta, interleukin-6 (IL-6), interleukin-8 (IL-8) and monocyte-attracting chemokines. This paper reviews: (1) in vivo examinations of the cytokine profiles during influenza in mice, humans or swine; (2) in vivo data on the probable role of these cytokines; and (3) selected in vitro data on cytokine induction by the influenza virus. Examination of respiratory secretions of experimentally infected humans or animals revealed a brisk and concurrent rise in several of the cytokines mentioned. Moreover, peak cytokine levels directly correlated with virus replication and disease. In the mouse model, specific anti-cytokine strategies have further confirmed the role of cytokines in body temperature changes, anorexia and lung inflammation. However, cytokines were clearly not the only factor contributing to disease, and they seemed to be essential for resolution of the infection. Though influenza virus was shown to induce cytokines in cell culture, in vitro experiments have also revealed conflicting data. Furthermore, the viral genes or products that are responsible for cytokine induction are unknown. Exactly this information would make important contributions to our understanding of the genetic basis of viral virulence.

Charley B, Riffault S, Van Reeth K. Porcine innate and adaptative immune responses to influenza and coronavirus infections. Ann N Y Acad Sci. 2006 Oct;1081:130-6. PMID: 17135502

Both innate and adaptative immune responses contribute to the control of infectious diseases, including by limiting the spreading of zoonotic diseases from animal reservoirs to humans. Pigs represent an important animal reservoir for influenza virus infection of human populations and are also naturally infected by coronaviruses, an important group of viruses, which includes the recently emerged severe acute respiratory syndrome (SARS) virus. Studies on both innate and adaptative immune responses of pigs to influenza virus and coronaviruses contribute, therefore, to a better control of these infections in their natural hosts and will be briefly reviewed in this article. Pro-inflammatory cytokines, including type I interferon (IFN), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), were found in lung secretions of influenza virus infected pigs, and correlated with the intensity of clinical signs, whereas prior vaccination against influenza strongly reduced the production of infectious virus and cytokines in the lungs upon challenge, which was associated with clinical protection. An early type I IFN production was also found in coronavirus infected pigs, including at mucosal sites. IFN induction by < coronavirus is shown to involve interaction between a viral glycoprotein and a leukocyte subset, likely equivalent to plasmacytoid dendritic cells, present in the mucosae and associated lymphoid tissues. Given the IFN mediated antiviral and immunomodulatory effects, the use of IFN or IFN inducers may prove an efficient strategy for a better control of influenza virus and coronavirus infections in pigs. Because influenza and coronaviruses target mucosal surfaces, adaptative immune responses have to be characterized at mucosal sites. Thus, nasal and pulmonary antibody responses were analyzed in influenza virus infected or vaccinated pigs showing short-lived, but potentially protective local IgA and IgG antibody (Ab) responses. Interestingly, primary influenza virus infection induced long-lived increase of lung CD8(+) T cells and local lymphoproliferative responses. Pigs infected by a respiratory coronavirus (PRCV) showed virus-specific IgG Ab-secreting cells in the bronchial lymph nodes, whereas the transmissible gastroenteritis coronavirus (TGEV) induced more IgA Ab-secreting cells in gut tissues, which illustrates the importance of the route of antigen administration for inducing local immune effector mechanisms. Porcine viral infections provide, therefore, valuable models for evaluating the immune parameters that are important for controlling transmission of important viral zoonotic infections.