The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model

Abstract

Smallpox has played an unparalleled role in human history and remains a significant potential threat to public health. Despite the historical significance of this disease, we know little about the underlying pathophysiology or the virulence mechanisms of the causative agent, variola virus. To improve our understanding of variola pathogenesis and variola-host interactions, we examined the molecular and cellular features of hemorrhagic smallpox in cynomolgus macaques. We used cDNA microarrays to analyze host gene expression patterns in sequential blood samples from each of 22 infected animals. Variola infection elicited striking and temporally coordinated patterns of gene expression in peripheral blood. Of particular interest were features that appear to represent an IFN response, cell proliferation, immunoglobulin gene expression, viral dose-dependent gene expression patterns, and viral modulation of the host immune response. The virtual absence of a tumor necrosis factor ␣͞NF-B-activated transcriptional program in the face of an overwhelming systemic infection suggests that variola gene products may ablate this response. These results provide a detailed picture of the host transcriptional response during smallpox infection, and may help guide the development of diagnostic, therapeutic, and prophylactic strategies.

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

“…16 This nonhuman primate model for smallpox infection provides a detailed view of the in vivo host transcriptional program in peripheral blood (PB) after infection. Because the microarrays used in this study were of the same platform as the ones used in the present study, we could make a direct comparison.…”

“…Two-way hierarchical clustering was performed on genes that are significantly changed in expression after smallpox infection of macaques. 16 Data from the smallpox study were combined with expression data from RA patients and healthy controls (see Materials and methods).…”

“…Application of published data from the nonhuman primate model of smallpox A genome-wide investigation of poxvirus infection in macaques was performed by Rubins et al 16 In this study, PBMCs were obtained from macaques before and after infection with smallpox virus. Gene expression data were obtained using the same microarray platform and data were filtered as described above.…”

Transcriptional profiling of the peripheral blood response during tularemia

“…2 In a macaque model of smallpox, generalized responses representing IFN-regulation genes, cell proliferation genes and immunoglobulin genes were observed. 1 However, also a lack of proinflammatory response involving TNF-a-and NF-kBdependent genes was noted, suggesting that smallpox may abrogate this response. The findings from such diverse models support the hypothesis that the various forms of sepsis and other infectious diseases share host effector pathways, 2 but also demonstrate that subversion of specific immune functions may be pathognomonic of certain diseases.…”

“…For example, the molecular and cellular features of hemorrhagic smallpox in macaques have been analyzed by use of cDNA microarrays and certain unique features were identified. 1 In a murine model of sepsis, the transcriptional response of peripheral blood cells (PBC) was undertaken. 2 Some 5% of assessed genes were differentially regulated and most of the genes were present in both Gram-negative and Gram-positive sepsis.…”