Respiratory viruses and eosinophils: exploring the connections

Abstract

In this review, we consider the role played by eosinophilic leukocytes in the pathogenesis and pathophysiology of respiratory virus infection. The vast majority of the available information on this topic focuses on respiratory syncytial virus (RSV; Family Paramyxoviridae, genus Pneumovirus), an important pediatric pathogen that infects infants worldwide. There is no vaccine currently available for RSV. A formalin-inactivated RSV vaccine used in a trial in the 1960s elicited immunopathology in response to natural RSV infection; this has been modeled experimentally, primarily in inbred mice and cotton rats. Eosinophils are recruited to the lung tissue in response to formalin-inactivated RSV vaccine antigens in humans and in experimental models, but they may or may not be involved in promoting the severe clinical sequelae observed. Pulmonary eosinophilia elicited in response to primary RSV infection has also been explored; this response is particularly evident in the youngest human infants and in neonatal mouse models. Although pulmonary eosinophilia is nearly always perceived in a negative light, the specific role played by virus-elicited eosinophils - negative, positive or neutral bystander - remain unclear. Lastly, we consider the data that focus on the role of eosinophils in promoting virus clearance and antiviral host defense, and conclude with a recent study that explores the role of eosinophils themselves as targets of virus infection.

Fig. 1

Eosinophils. (A) Human eosinophils isolated from peripheral blood by negative selection and (B) mouse eosinophils detected in bone marrow.

Fig. 2

Hypersensitivity responses in mice vaccinated with formalin-fixed pneumovirus antigens. (A) Lung tissue from a mouse vaccinated with formalin-inactivated pneumonia virus of mice (PVM; a mouse pneumovirus related to human RSV) and then challenged intranasally with actively replicating virus (B) Eosinophils detected in bronchoalveolar lavage fluid from the mouse described in (A); (C) percentage eosinophils detected in bronchoalveolar lavage fluid in mice vaccinated with formalin-inactivated PVM vs. control antigen. Panels (A) and (B) reprinted with permission from Percopo et al. (2009).

Fig. 3

Detection of eosinophil granule proteins in lung washings from infants diagnosed with RSV. Concentrates of lung washings from infants undergoing ventilatory support for ELISA-confirmed severe RSV disease (lanes 1–10) probed with antibodies against eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP); lanes 11–12, concentrates of lung washings from infants ventilated secondary to other causes, +C, positive control. Reprinted with permission from Harrison et al. (1999).

Fig. 4

Eosinophils promote antiviral host defense. (A) Eosinophils reduce the infectivity of RSV for target epithelial cells in vitro; (B) eosinophil-enriched interleukin-5 transgenic mice promote accelerated RSV clearance compared to wild type mice, with reduced virus titers detected at all time points examined. Panels (A) and (B) reprinted with permission from Domachowske et al. (1998) and Phipps et al. (2007), respectively.

Fig. 5

Pneumovirus replication in eosinophils. Cultured eosinophils derived from mouse bone marrow (A) stained with modified Giemsa and (B) stained with anti-mouse MBP antibody. (C) Replication of PVM in cultured mouse eosinophils; filled symbols, replication competent PVM; open symbols, heat-inactivated PVM. PVM is detected by quantitative RT-PCR targeting the virus SH gene. (D) Replication of PVM in cultured mouse eosinophils is accompanied by the replication-dependent release of interleukin-6; reprinted with permission from Dyer et al. (2008).