Cyclosporin A alleviates influenza A (H1N1) virus-induced chronic pulmonary inflammation through decreasing IFN-γ-producing T lymphocytes 2025 Deng+

[Andy]

Abstract​

Influenza causes 3–5 million severe cases globally each year, with severe viral pneumonia often requiring hospitalization for over four weeks. While the inflammatory response to influenza infection helps control viral replication, excessive inflammation is a key driver of disease severity and mortality. Excessive pulmonary lymphocytes, particularly IFN-γ-producing T lymphocytes, contribute significantly to pulmonary inflammation at the late-stage of H1N1 viral infection. Cyclosporin A, a potent T-cell inhibitor, mitigates influenza A virus-induced pulmonary inflammation in mice. However, the therapeutic role of lymphocyte suppression in cyclosporin A-mediated attenuation of H1N1 virus-induced chronic pulmonary inflammation remains unclear.

Here, we demonstrated that the viral titer was 0 in all the homogenized lung tissues of mice on Day-21 post a sublethal H1N1 viral infection. H1N1 viral infection caused worsened general condition and pulmonary inflammation with the infiltration of lymphocytes and neutrophils on Day-21 post-infection. The bronchoalveolar lavage fluid of H1N1 virus-infected mice showed a 16-fold higher lymphocyte count compared to neutrophils. H1N1 viral infection significantly elevated both IFN-γ-producing T lymphocyte populations and IFN-γ levels in mouse lungs. H1N1 viral infection additionally expanded IFN-γ-producing T lymphocyte populations in both spleen and peripheral blood. Cyclosporin A treatment significantly mitigated H1N1 viral infection-induced worsened general condition, pulmonary lymphocytic inflammation, increases of pulmonary IFN-γ concentrations and IFN-γ-producing T lymphocytes in the lung, spleen and blood of mice on Day-21 post-infection.

Together, lymphocytes may contribute significantly to H1N1 virus-induced chronic pulmonary inflammation. Cyclosporin A may alleviate H1N1 virus-induced chronic pulmonary inflammation through decreasing IFN-γ-producing T lymphocytes.

Open access

 

[jnmaciuch]

The “may” in the final sentence is carrying a lot of weight here, since the paper didn’t prove that the effects of cyclosporin A in their mouse model are mediated solely by its effect on T cells.

Most papers will claim that Cyclosporin A affects T cells by binding to calcineurin—modulating the calcium metabolism that bridges T cell receptor binding with the downstream interferon gamma response. But Cyclosporin A also blocks the MTP—a pore that forms in the mitochondrial membrane under energetic stress and releases mtDNA, which then triggers cytosolic DNA sensors.

This secondary mechanism is what triggers interferon production—we know it works this way for interferon alpha and beta in tissue cells, and that T cells use this pathway as well for interferon gamma production. We know that Cyclosporin A inhibits type I interferon production in tissue cells in addition to its action on T cells.

The findings of this paper cannot differentiate between either possibility. They are probably related, as local type I interferon production will result in chemokine production that calls in lymphocytes and stimulates their differentiation. And there is good reason to think that lymphocyte infiltration further worsens pulmonary condition.

But the title of this paper claims something they haven’t proven, which is that Cyclosporin A improves pulmonary inflammation during infection specifically, or even primarily, through its effects on T cells.

In order to prove their claim, they should have used other drugs that deplete T cells by another mechanism, and show that in all cases, decreased T cell infiltration produces the same improvement in clinical presentation. I don’t know why this paper didn't test other T cell targeting drugs, I feel like it should have been the first thing any good reviewer would have asked for. Perhaps they did do this and it just didn’t show the results they wanted.