Adenovirus Infection Dramatically Augments Lipopolysaccharide-Induced TNF Production and Sensitizes to Lethal Shock

Abstract

We observed a remarkable synergism of adenoviruses and LPS in triggering the production of TNF in intact animals. We found that in mice pre-exposed to adenoviruses, LPS injections generated extremely high levels of TNF with altered kinetics. The elevated TNF synthesis stemmed mostly from posttranscriptional up-regulation of TNF production, although transcription of the TNF gene was also induced. Adenoviruses and LPS exhibited a significant but less dramatic synergism in the induction of IL-6, IFN-γ, and NO. Only marginal changes were detected in the synthesis of a panel of other cytokines. Different serotypes of the virus showed practically identical effects. As deletion mutants lacking indispensable viral genes or UV inactivated virions exhibited similar activities as the infectious, wild-type virus, it seems unlikely that the viral genome plays any significant role in the phenomenon. Published data indicate that other viruses also show some kind of synergism with LPS, although by different cellular mechanisms. T cells and their IFN-γ production—crucial in the synergism of influenza viruses and LPS—were dispensable in our experiments. We suggest that the phenomenon is probably a general one: an overlap between different molecular mechanisms detecting bacterial and viral pathogens and inducing mediators of nonspecific cell-mediated host defense. The synergism of viruses and LPS (bacteria) could be a concern in medical practice as well as in gene therapy experiments with high doses of recombinant adenoviruses.

Malaria primes the innate immune response due to interferon-γ induced enhancement of toll-like receptor expression and function

“…As IFN␥ is not produced in abundance by phagocytes, and is expressed in mouse lymphocytes (26), the mechanism appears to involve cross talk between the innate and the acquired arms of the immune system. IFN␥ has been shown not only to increase TLR expression but also to prime cells to LPS responses in a number of experimental infections (27)(28)(29)(30) and has also been pointed as crucial to prime macrophages to release high amounts of TNF upon LPS administration and contribute to LPS induced septic shock (31). We (12) and others (14) have shown that TLR9 accounts for a considerable amount of IFN␥ produced during malaria.…”

Development of an interferon-γ release assay (IGRA) for detection of Brucella abortus and clinical diagnosis of brucellosis

“…Suboptimal concentration of IFN-γ does not trigger immune cells, instead, it primes for subsequent response upon stimulation, but, in excess, can eventually cause deleterious consequences. This IFN-γ priming effect has been increasingly implicated in the immune response to several infectious diseases, including viral, bacterial, and parasitic diseases [12][13][14]. For brucellosis, the crucial role of IFN-γ was recognized, as it was shown that IFN-γ knockout mice died due to B. abortus infection and IFN-γ producing CD4+ T-cells from infected donors were able to protect the recipient mice against challenge with B. abortus [15].…”

Adenovirus-triggered innate signalling pathways

“…In contrast, Ad-induced early-type I IFN production mediates a very strong LPS hypersensitivity characterized by the dramatic overproduction of TNF (50-100-fold) and IL-6 (5-10-fold) [88]. Furthermore, there is a strong overproduction of nitric oxide (NO), mostly in spleen [88]. Interestingly, LPS injection of uninfected control animals elicits NO production mainly in liver.…”

“…In these cases, early production of IFN-αβ 2-3 days after infection mediates a relatively weak (2-4-fold) hypersensitivity (or even downregulation of TNF production ) [92], while later (after 7 days) IFN-production mediates a strong hypersensitivity to LPS, characterized by the overproduction of TNF [89][90][91][92][93]. In contrast, Ad-induced early-type I IFN production mediates a very strong LPS hypersensitivity characterized by the dramatic overproduction of TNF (50-100-fold) and IL-6 (5-10-fold) [88]. Furthermore, there is a strong overproduction of nitric oxide (NO), mostly in spleen [88].…”

“…The best studied example is the induction of hypersensitivity to bacterial endotoxin (LPS) [88]. Other viruses such as Lymphocytic Choriomeningitis Virus (LCMV) have also been shown to induce LPS hypersensitivity.…”