Thyroid hormone deficiency worsens outcomes in vaccinia virus infection

Intranasal inhalation of the vaccinia virus in mice leads to acute lung infection followed by peripheral organ damage. Our findings demonstrate that hypothyroidism significantly exacerbates disease severity. Hypothyroid mice exhibit higher disease scores, elevated lung viral loads, and more extensive tissue damage in both the lungs and peripheral organs. Notably, only hypothyroid mice reach the experimental endpoint, underscoring their heightened vulnerability. Hypothyroid mice display a defective splenic immune response, with no amplification of T and B lymphocytes, but the increased susceptibility to vaccinia virus infection also persists in hypothyroid lymphocyte-deficient Rag2^-/- mice. Prior to infection, hypothyroid mice show a reduced pool of lung alveolar macrophages, and lung viral loads are significantly elevated in these animals as early as 1 day post-infection, suggesting that an impaired innate immune response is involved in their increased susceptibility to vaccinia virus. Indeed, transfer of primary alveolar macrophages into the alveolar macrophage-deficient lungs of hypothyroid mice significantly alleviates disease symptoms. In euthyroid mice, circulating thyroid hormone levels decrease during infection, a well-documented response in sepsis and critical illness, known as non-thyroidal illness syndrome. Further highlighting the link between thyroid hormones and immune defense, we show that SRT1720, a Sirtuin 1 activator, reduces thyroid hormone levels and also worsens vaccinia infection when administered to euthyroid mice. In summary, our study reveals that hypothyroidism aggravates vaccinia virus infection. While the role of thyroid hormone decline in various diseases remains a topic of debate, our results suggest that thyroid hormones play a protective role in viral pulmonary infections.IMPORTANCEVaccinia virus serves both as a recombinant vaccine platform and as a model for studying human smallpox and monkeypox infections, which are associated with high mortality rates. Here, we show that hypothyroidism in mice aggravates the severity of vaccinia virus infection due to a deficient splenic immune response and to a marked reduction in lung alveolar macrophages, a key cell population in defense against respiratory pathogens. Intratracheal administration of primary alveolar macrophages improves disease symptoms during the early phase of infection in hypothyroid animals. Hypothyroidism also impairs the amplification of splenic lymphocytes, which play a key role in defense against viral infection. Furthermore, vaccinia virus infection reduces thyroid hormone levels in euthyroid mice, a phenomenon named "non-thyroidal illness syndrome" that often occurs in septic patients, suggesting that, in the context of viral pulmonary infections, thyroid hormone replacement might be a useful therapeutic option.