Innate immune responses to influenza A H5N1: friend or foe?

Abstract

Avian influenza A H5N1 remains unusual in its virulence for humans. Although infection of humans remains inefficient, many of those with H5N1 disease have a rapidly progressing viral pneumonia that leads to acute respiratory distress syndrome and death, but its pathogenesis remains an enigma. Comparison of the virology and pathogenesis of human seasonal influenza viruses (H3N2 and H1N1) and H5N1 in patients, animal models and relevant primary human cell cultures is instructive. Although the direct effects of viral replication and differences in the tropism of the virus for cells in the lower respiratory tract clearly contribute to pathogenesis, we focus here on the possible contribution of the host innate immune response in the pathogenesis of this disease.

Figure 1

(A) Lung histology of fatal human H5N1 disease stained with Haematoxylin & Eosin showing increased cellular inflammation within the alveoli compared to normal lung. (B) Immunohistochemistry for the macrophage marker CD68 (brown) shows increased numbers of macrophages infiltrating the lung tissue. (C) The histological appearance and alveolar macrophages shown by CD68 immunohistochemistry in a control lung is shown for comparison. Magnification × 200.

Figure 1

(A) Lung histology of fatal human H5N1 disease stained with Haematoxylin & Eosin showing increased cellular inflammation within the alveoli compared to normal lung. (B) Immunohistochemistry for the macrophage marker CD68 (brown) shows increased numbers of macrophages infiltrating the lung tissue. (C) The histological appearance and alveolar macrophages shown by CD68 immunohistochemistry in a control lung is shown for comparison. Magnification × 200.

Figure 1

(A) Lung histology of fatal human H5N1 disease stained with Haematoxylin & Eosin showing increased cellular inflammation within the alveoli compared to normal lung. (B) Immunohistochemistry for the macrophage marker CD68 (brown) shows increased numbers of macrophages infiltrating the lung tissue. (C) The histological appearance and alveolar macrophages shown by CD68 immunohistochemistry in a control lung is shown for comparison. Magnification × 200.

Figure 2

Mechanisms that may contribute to the pathogenesis of H5N1 disease. Arrows indicate the factors contributing to outcome. Higher levels of viral replication, the binding of the H5N1 virus to receptors in alveolar epithelial cells, and the spread of the virus beyond the respiratory tract could all contribute to the severity of human H5N1 disease. In this review, we argue that the H5N1 virus differentially activates host responses in macrophages and primary lung alveolar epithelia and such differences in host responses contribute to disease pathogenesis. This figure is modified from reference .

Figure 3

Cytokine and chemokine induction in macrophages infected with H5N1 virus. Virus infection activates interferon regulatory factor 3 (IRF-3) and the p38-MAPK signaling pathways as well as others. Activation of these pathways leads to the expression of primary mediators such as tumor necrosis factor- α (TNF-α), the type I interferons (IFN)-α and -β which in turn trigger release of other cytokines and chemokines through autocrine and paracrine effects. Cyclooxygenase-2 (COX-2) is involved in regulating cytokine expression within the infected cell, as well as those activated by secreted mediators in adjacent uninfected cells.

Figure 4

Proinflammatory cascades in the pathogenesis o f lung damage in H5N1 disease. (1) Virus infection of macrophages and alveolar epithelium leads to virus replication as well as release of cytokines and chemokines (2), which trigger autocrine and paracrine proinflammatory cascades involving both cell types and infected as well as uninfected cells. These host responses are more potently induced by H5N1 virus compared to seasonal influenza viruses. Some of these cytokines (e.g. interferons) are expected to have an antiviral effect, but the overall effects of these cytokine cascades may well contribute to pathogenesis. The amplification cascade involving adjacent uninfected cells leads to a faster and broader inflammatory response than that induced by direct virus infection. (3) Chemokines lead to the infiltration of inflammatory cells (lymphocytes, monocytes/macrophages, neutrophils, and dendritic cells) into the alveolar spaces thereby further amplifying these proinflammatory cascades (4). Infiltration of tipDCs (TNF-α/inducible nitric oxide synthase [iNOS] producing DCs) into the alveolar space leads to proliferation of influenza-specific CD8⁺ cytotoxic T-cells in the lung (5). These CD8⁺ cells are important for the control of the virus infection, but in excessive numbers, may also contribute to tissue damage. (6) Virus may also infect and replicate in myeloid DCs and this may possibly allow virus to be disseminated by these cells to other organs and tissues.