Attenuated Response of Aged Mice to Respiratory Francisella novicida Is Characterized by Reduced Cell Death and Absence of Subsequent Hypercytokinemia

Abstract

BackgroundPneumonia and pulmonary infections are major causes of mortality among the growing elderly population. Age associated attenuations of various immune parameters, involved with both innate and adaptive responses are collectively known as immune senescence. These changes are likely to be involved with differences in host susceptibility to disease between young and aged individuals.Methodology/Principal FindingsThe objective of this study was to assess potential age related differences in the pulmonary host response in mice to the Gram-negative respiratory pathogen, Francisella novicida. We intranasally infected mice with F. novicida and compared various immune and pathological parameters of the pulmonary host response in both young and aged mice.Conclusions/SignificanceWe observed that 20% of aged mice were able to survive an intranasal challenge with F. novicida while all of their younger cohorts died consistently within 4 to 6 days post infection. Further experiments revealed that all of the aged mice tested were initially able to control bacterial replication in the lungs as well as at distal sites of replication compared with young mice. In addition, the small cohort of aged survivors did not progress to a severe sepsis syndrome with hypercytokinemia, as did all of the young adult mice. Finally, a lack of widespread cell death in potential aged survivors coupled with a difference in cell types recruited to sites of infection within the lung confirmed an altered host response to Francisella in aged mice.

Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

“…infection (5,12,13). Consistent with previous reports, we observed a robust inflammatory response, particularly at 48 and 72 h postinfection in the LVS-infected mice (3,5,12,13,21,22). In contrast, the Fpt mutant strains induced significantly less proinflammatory gene expression, and this reduction correlated with lower bacterial burdens and reduced pathology.…”

“…In contrast, the Fpt mutant strains induced significantly less proinflammatory gene expression, and this reduction correlated with lower bacterial burdens and reduced pathology. It was shown previously that a cytokine storm resulting in severe tissue damage is a factor contributing to F. tularensis virulence in mice (3,21,22,38). The reduced induction of gene expression of the proinflammatory cytokines TNF-␣, IFN-␥, and iNOS in the livers of mice infected with Fpt mutant strains corresponded to decreased liver pathology compared with that of mice infected with LVS, where more inflammatory foci, apoptosis, and necrosis were observed.…”

“…Since the pathology induced by LVS has been attributed to the ability of this organism to produce an early cytokine storm (5,21,22), we hypothesized that the attenuated Fpt mutants would also exhibit a diminished early proinflammatory response. Livers from LVS-infected mice showed significantly increased levels of cytokine and iNOS mRNAs over a 24-to 72-h period, as previously reported (5,6).…”

The future of murine sepsis and trauma research models

“…For example, sepsis is an increasingly significant problem throughout the world, and infections remain 1 of the top causes of poor outcomes [1,2]. Severe sepsis and septic shock have estimated in-hospital mortalities of 29-40% and .50%, respectively [3][4][5].…”

Toll-like Receptor function of murine macrophages, probed by cytokine induction, is biphasic and is not impaired globally with age

“…Susceptibility to bacterial pathogens, in general, also increases with age (Gardner & Remington, 1977), due to reduced T cell reactivity and diminished innate immune functions of myeloid cells (Løvik & North, 1985; Patel, 1981). The enhancement with advancing age of resistance to Listeria monocytogenes (Emmerling et al, 1979; Matsumoto et al, 1979) and Francisella novicida (Mares et al, 2010), in contrast, reflect paradoxical aging-associated immune alterations.…”