Innate Immune Dysfunctions in Aged Mice Facilitate the Systemic Dissemination of Methicillin-Resistant S. aureus

Abstract

Elderly humans show increased susceptibility to invasive staphylococcal disease after skin and soft tissue infection. However, it is not understood how host immunity changes with aging, and how that predisposes to invasive disease. In a model of severe skin infection, we showed that aged mice (16- to 20-month-old) exhibit dramatic bacterial dissemination compared with young adult mice (2-month-old). Bacterial dissemination was associated with significant reductions of CXCL1 (KC), polymorphonuclear cells (PMNs), and extracellular DNA traps (NETs) at the infection site. PMNs and primary skin fibroblasts isolated from aged mice showed decreased secretion of CXCL2 (MIP-2) and KC in response to MRSA, and in vitro analyses of mitochondrial functions revealed that the mitochondrial electron transport chain complex I plays a significant role in induction of chemokines in the cells isolated from young but not old mice. Additionally, PMNs isolated from aged mice have reduced ability to form NETs and to kill MRSA. Expression of nuclease by S. aureus led to increased bacterial systemic dissemination in young but not old mice, suggesting that defective NETs formation in elderly mice permitted nuclease and non-nuclease expressing S. aureus to disseminate equally well. Overall, these findings suggest that gross impairment of both skin barrier function and innate immunity contributes to the propensity for MRSA to disseminate in aged mice. Furthermore, the study indicates that contribution of bacterial factors to pathogenicity may vary with host age.

Sex, the aging immune system, and chronic disease

“…Aged NK cells exhibit decreased cytotoxicity and produce lower levels of cytokines [72]. Neutrophils from aged hosts consistently show impairments in the phagocytosis of opsonized bacteria and the ability to kill phagocytosed microorganisms which appear to be dependent upon age-related diminishment of CD16 expression [73][74][75][76][77][78][79][80][81].…”

What role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia?

“…The ability of S. aureus to escape from neutrophils is likely crucial for infection in relatively healthy individuals with well-functioning immune systems. However, in patients with impaired immune function (e.g., diabetics and the elderly), the importance of neutrophil escape, and thus Agr function, may be significantly diminished [3,[88][89][90]. Therefore, under conditions of high antibiotic exposure such as those found in healthcare settings, coupled with a highly susceptible host population (broken skin or compromised immune function), it may be advantageous for S. aureus to sacrifice Agr activity for antibiotic resistance (Figure 3).…”

Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals

“…Indeed, as a result of impairments in several defensive strategies such as phagocytosis (Wenisch et al ., 2000; Butcher et al ., 2001), degranulation (McLaughlin et al ., 1986) and ROS production (Fulop et al ., 2004), the microbicidal activity of neutrophils from older adults is markedly reduced (Wenisch et al ., 2000; Simell et al ., 2011). Recently, Tseng and colleagues (Tseng et al ., 2012) made the novel observation that NET formation is also impaired with age, with the group demonstrating neutrophils from aged mice generated significantly fewer NETs when challenged with Staphylococcus aureus (Tseng et al ., 2012). In vivo , this defect in NET generation was associated with marked bacteraemia, leading the group to hypothesize that aberrant NET formation may explain why older adults are more susceptible to invasive bacterial disease following skin and soft tissue infection (Tseng et al ., 2012).…”

“…Recently, Tseng and colleagues (Tseng et al ., 2012) made the novel observation that NET formation is also impaired with age, with the group demonstrating neutrophils from aged mice generated significantly fewer NETs when challenged with Staphylococcus aureus (Tseng et al ., 2012). In vivo , this defect in NET generation was associated with marked bacteraemia, leading the group to hypothesize that aberrant NET formation may explain why older adults are more susceptible to invasive bacterial disease following skin and soft tissue infection (Tseng et al ., 2012). However, the study did not investigate the impact of physiological aging on NET generation by human neutrophils or the mechanisms involved.…”