https://www.gastrojournal.org/article/0016-5085(92)91122-K/pdf

Serum levels of cytokines in chronic liver diseases.

To further understand the role of cytokine responses in symptom formation and host defenses in influenza infection, we determined the levels of IL-1beta, IL-2, IL-6, IL-8, IFN-alpha, TGF-beta, and TNF-alpha in nasal lavage fluid, plasma, and serum obtained serially from 19 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) and correlated these levels with various measures of infection and illness severity. We found that IL-6 and IFN-alpha levels in nasal lavage fluids peaked early (day 2) and correlated directly with viral titers, temperature, mucus production, and symptom scores. IL-6 elevations were also found in the circulation at this time point. In contrast, TNF-alpha responses peaked later (day 3 in plasma, day 4 in nasal fluids), when viral shedding and symptoms were subsiding. Similarly, IL-8 peaked late in the illness course (days 4-6) and correlated only with lower respiratory symptoms, which also occurred late. None of IL-1beta, IL-2, or TGF-beta levels increased significantly. These data implicate IL-6 and IFN-alpha as key factors both in symptom formation and host defense in influenza.

/pdf/local-and-systemic-cytokine-responses-during-experimental-3xwlkx1o0i.pdf

Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense.

Influenza A viruses that circulate normally in the human population cause a debilitating, though generally transient, illness that is sometimes fatal, particularly in the elderly. Severe complications arising from pandemic influenza or the highly pathogenic avian H5N1 viruses are often associated with rapid, massive inflammatory cell infiltration, acute respiratory distress, reactive hemophagocytosis and multiple organ involvement. Histological and pathological indicators strongly suggest a key role for an excessive host response in mediating at least some of this pathology. Here, we review the current literature on how various effector arms of the immune system can act deleteriously to initiate or exacerbate pathological damage in this viral pneumonia. Generally, the same immunological factors mediating tissue damage during the anti-influenza immune response are also critical for efficient elimination of virus, thereby posing a significant challenge in the design of harmless yet effective therapeutic strategies for tackling influenza virus.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.icb.7100026

A question of self-preservation: immunopathology in influenza virus infection.

The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles

Intranasal inoculation of type 5 adenovirus (Ad5) produced pneumonia in mice even though the virus did not replicate. To induce the pneumonia, however, a large viral infectious dose was required--i.e., 10(10) plaque-forming units. Four strains of inbred mouse were studied (C57BL/6N, C57BL/10ScN, CBA/N, and C3H/N): all showed similar inflammatory responses, although the greatest infiltration occurred in the C57BL/6N mice. The pathological response to Ad5 infection resembled that previously described in cotton rats: it consisted of overlapping early and late phases, and the infiltration contained primarily lymphocytes and monocytes/macrophages with a scattering of polymorphonuclear leukocytes. The prominent early phase and the presence of polymorphonuclear leukocytes suggested that induction of cytokines may play an important role in the pathogenesis of this pneumonia. Assays showed the appearance of tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), and IL-6 in the infected mouse lungs concomitant with the developing early-phase infiltration. Only IL-6 was found in the peripheral blood. IL-6 reached maximum titers 6-24 hr after infection, whereas maximum levels of TNF-alpha and IL-1 were attained 2-3 days after infection. Specific RNAs for each of these cytokines were demonstrated in the infected lungs. To test the hypothesis that a cytotoxic T-cell response was responsible for the second phase, which primarily consisted of a perivascular and peribronchial infiltration of lymphocytes, Ad5 was used to infect C57BL/10ScN Nu/Nu and parent mice. The nude mice showed a normal early-phase response, but essentially no peribronchial and only minimal perivascular infiltrations occurred.

https://www.pnas.org/content/pnas/88/5/1651.full.pdf

A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia.

Influenza A virus infections are commonly associated with symptoms that suggest involvement of TNF-alpha. In this study, we exposed human monocytes, rat alveolar macrophages, and murine PU5-1.8 macrophages to influenza A virus, strain Puerto Rico 8. We observed a productive infection that was accompanied by TNF-alpha mRNA accumulation, TNF-alpha release and subsequent cell death. TNF-alpha production was dependent on exposure to live virus, in contrast to IFN release that was also induced by UV-inactivated virus. Most strikingly, low amounts of LPS (1 to 10 ng/ml) from Escherichia coli or Haemophilus influenzae were capable of strongly potentiating TNF-alpha production from virus-infected macrophages. The potentiating effect of LPS was neither due to increased survival of macrophages nor to altered virus multiplication, enhanced TNF-alpha gene expression, discharge of intracellular TNF-alpha stores, or shifts in the kinetics of TNF-alpha release. Thus, low amounts of LPS, which could easily be present in vivo, may serve as a potent trigger signal for TNF-alpha production from macrophages that have been primed by influenza A virus infection. These data suggest that the frequently observed serious complications of combined influenza A virus and bacterial infections may be partially due to a high TNF-alpha production.

Tumor necrosis factor-alpha production of influenza A virus-infected macrophages and potentiating effect of lipopolysaccharides.

We have previously shown that infection of macrophages by influenza A virus is capable of priming for a high TNF-alpha production in response to LPS. The present study was designed to examine in more detail TNF-alpha gene expression and TNF-alpha protein release of virus-infected, murine PU5-1.8 macrophages in the presence or absence of low and by itself rather inefficient concentrations of LPS (10 ng/ml). Although influenza A virus infection alone induced a massive TNF-alpha mRNA accumulation, translation into the bioactive TNF-alpha protein was low as intra- and extracellularly determined by bioassay, specific ELISA and Western blot. However, when LPS was added simultaneously or up to 4 h after infection, a high TNF-alpha production was initiated. The virus-induced TNF-alpha mRNA accumulation appeared to be due to both transcriptional and post-transcriptional changes: an enhanced TNF-alpha gene transcription as determined by nuclear run-on transcription assay and a markedly prolonged half-life of TNF-alpha mRNA as shown in actinomycin D-treated macrophages. These findings imply that influenza A virus may 1) either directly or indirectly stimulate TNF-alpha gene transcription activators or may interfere with labile transcription repressor proteins and 2) may stabilize TNF-alpha mRNA by delaying its degradation. Both mechanisms, taken together, prime influenza A virus-infected macrophages for a high TNF-alpha release in response to LPS which, as clinical cases show, may adversely affect patients with combined influenza A virus and bacterial infections.

Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release.

F. Hinder

Papers

Tumor necrosis factor-alpha production of influenza A virus-infected macrophages and potentiating effect of lipopolysaccharides.

Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release.