**3.4. Sex-specific mechanisms of infection and immunity**

regard, strains from least to most sensitive include BALB/c, DBA/2, C57BL/6, NIH, AKR, FVB/N, CSH/He, SJL, and CBA/Ca [103]. The majority of inbred mouse strains are resistant to infection with *L. pneumophila*, however, A/J mice carry the Lgn1-s allele, making them sus-

Currently, researchers are taking advantage of the phenotypic and genetic variations available in CC mice. The CC combines the genomes of eight genetically diverse founder strains, such as A/J, C57BL/6 J, 129S1/SvImJ, NOD/LtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/ EiJ [85]. This genetic combination is a significant element for the study on human-host susceptibility to major diseases, including infections, such as pneumonia [105]. In a recent study, scientists used the CC mouse model to determine whether the host genetic background could impact the risk of morbidity and mortality to pneumonia caused by infection with *P. aeruginosa*. In this study, the CC strain reproduced the responses of disease severity commonly observed in humans during infection, suggesting that variations in morbidity and mortality are highly affected by host genetic factors [105]. Whereas no significant gender differences on disease phenotypes were observed, it is important to note the sample size was small. Similar variations in morbidity and mortality were found in another study where scientists used CC animals to perform a quantitative trait locus mapping of host susceptibility to *Klebsiella* sp. infection in a study where females were found to be less susceptible to infection than males [106]. In summary, animal models with high genetic diversity, and large size and number of independent recombination are emerging as a powerful tool for genomic studies, helping scientists better understand and develop more effective therapies for pneumonia [107].

It has been known for several years that sex is a contributing factor in the prevalence and development of a number of pulmonary diseases, such as pneumonia [11, 108]. Animal studies also suggest that there is a sexual dimorphism after puberty in innate and adaptive immune response genes in C57BL/6 mice, with innate immune response genes being highly upregulated in postpubertal male mice but not in female mice. In contrast, postpubertal female mice express high levels of adaptive immune response genes, and expression of these genes occurs

Several studies in animals have reported that increase in circulating levels of estrogens may lead to reduced innate immunity, as measured by natural killer cell and macrophage activity, and a decrease of cytokine release [109–111]. Animal models of infection are the simplest tool available to study sex differences due to high availability of castrated animals and hormonal replacement therapies. Multiple studies have demonstrated that susceptibility to invasive viral, bacterial, fungal, and parasitic diseases is higher in males than in females in all age groups [57, 61, 112, 113]. The concept that males are more susceptible to lung infection is further sustained by data from mouse models of bacterial infection, such as *Pneumococcal pneumonia* and *Mycobacterium marinum*, where female mice display longer survival than male mice when exposed to severe sepsis [62, 114]. Infection of C57BL/6 mice with *K. pneumoniae* demonstrated a severe effect in male mice, but not in female mice [19]. In contrast, after infection with *P. aeruginosa*, C57BL/6 female mice showed greater weight loss, bacterial load, and

ceptible to infection [104].

12 Contemporary Topics of Pneumonia

**3.3. Sex differences in pneumonia models**

at lower levels in postpubertal male mice [60].

Currently, there is limited understanding of the molecular processes that lead to either immune-suppression or stimulation during pneumonia pathogenesis in males and females. In general, females display strong humoral immune responses after infection or vaccination when compared to males [114]. This is partially due to high levels of CD4+ T cells and variations in regulatory T cells (Treg) that regulate immune responses during the menstrual cycle in women [117]. It is known that estrogen influences transcription of specific genes that alter host immunity and promotes the proliferation of Treg during the follicular phase of the ovarian cycle [89, 118]. Because estrogen regulates CD4+ T cell subsets, there is a direct effect on Th1/Th2 equilibrium known to be crucial against bacterial and viral infections. On the other hand, studies indicate that negative outcomes from infectious pulmonary diseases in males is associated with testosterone-induced immunosuppression causing a decrease in T and B cell proliferation, and immunoglobulin and cytokine production after puberty [14]. These alterations in the adaptive immune system could help explain why men are more susceptible than women to some pulmonary diseases caused by infectious agents. However, treatments for pneumonia are standardized for both men and women indicating a general lack of understanding of sex-based differences.
