Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6

Abstract

Eosinophils are recruited to the lung in response to infection with pneumovirus pathogens and have been associated with both the pathophysiologic sequelae of infection and, more recently, with accelerated virus clearance. Here, we demonstrate that the pneumovirus pathogens, respiratory syncytial virus (RSV) and pneumonia virus of mice (PVM), can infect human and mouse eosinophils, respectively, and that virus infection of eosinophils elicits the release of diseaserelated proinflammatory mediators from eosinophils. RSV replication in human eosinophils results in the release of infectious virions and in the release of the proinflammatory mediator, interleukin-6 (IL-6). PVM replication in cultured bone marrow eosinophils (bmEos) likewise results in release of infectious virions and the proinflammatory mediators IL-6, IP-10, CCL2, and CCL3. In contrast to the findings reported in lung tissue of RSVchallenged mice, PVM replication is accelerated in MyD88 gene-deleted bmEos, whereas release of cytokines is dimin- IntroductionEosinophils are unique proinflammatory leukocytes that are easily recognized but poorly understood. Although eosinophil expansion in the bone marrow and recruitment from the bloodstream to peripheral tissues are prominent findings that are clearly associated with asthma, allergic diseases, and infection with helminthes, there is no full consensus about the physiologic or pathophysiologic roles played by eosinophils in any of these disease states. [1][2][3] Interestingly, among the many points that have emerged from the clinical studies featuring therapeutic administration of antiinterleukin 5 (IL-5) monoclonal antibody (mepolizumab), 4-7 it has become evident that we have a very limited understanding of the subtleties of eosinophil recruitment and function; this limited understanding may relate to a long-standing focus on numbers of eosinophils recruited rather than on the nature, quality, and extent of eosinophil activation.With this in mind, we have focused our studies on the role of eosinophils and of eosinophil activation in acute respiratory virus infections, 8 specifically, infections with respiratory syncytial virus (RSV) and pneumonia virus of mice (PVM), a mouse pneumovirus pathogen that replicates the sequelae of the more severe forms of RSV infection in inbred strains of mice. 9,10 Several converging lines of evidence suggest that eosinophils recruited to the lungs in response to pneumovirus infection may have a direct effect on the outcome of disease. Among these findings, several groups have detected immunoreactive eosinophil degranulation products in bronchial washings of patients with the most severe forms of RSV infection, 11,12 and we and others have reported direct recruitment of eosinophils to the lungs of PVM-infected mice. 13-15 RSV and PVM infections of their respective target cells result in the production of numerous proinflammatory cytokines, including the eosinophil chemoattractants RANTES and macrophage inflammatory protein-1␣/CCL3, [16][17][18][19] and RSV-infected tar...

Eosinophils Promote Antiviral Immunity in Mice Infected with Influenza A Virus

“…Antiviral effector functions of eosinophils were demonstrated in other viral infections wherein viral burden and mortality were reduced in hypereosinophilic mice (20,36,37), and granule proteins reduced the infectivity of respiratory syncytial virus and PVM (17,18), but not SeV (37). Although virus-induced eosinophil PMD was previously thought to require allergen exposure (20), we show that PMD can occur in response to IAV alone, suggesting eosinophils have the ability to respond to IAV as dynamically as they do to allergens.…”

Activated mouse eosinophils protect against lethal respiratory virus infection

“…40 Zimmermann et al 41 compared the ova and Af sensitization challenge models directly to one another via DNA microarray; among the 236 transcripts unique to the Af sensitization and challenge model are those encoding several proinflammatory cytokines, including IL-1b, IL-1a, CCL3, and most notably, IL-6, which has already been shown to have an impact on virus-eosinophil interactions. 42 The precise mechanisms via which Af (but not ova) primes eosinophils to respond to virus infection remain to be explored. Of note, Davoine et al 43 reported that human eosinophils interact with parainfluenza virus and release peroxidase only when in coculture with antigen presenting cells and CD4…”

Respiratory Syncytial Virus Infection in Human Bone Marrow Stromal Cells

“…Another recent report shows that human eosinophils are targets of RSV infection, can support genome replication, and can release infectious virions (26). This observation raises the important question of where the infection of circulating blood cells may occur, either upon recruitment of mature leukocytes to the peripheral site of infection and inflammation (i.e., the lungs), in the bloodstream during a viremic episode, or rather at some stage of the maturation process within the bone marrow.…”