Fever and sickness behaviour during simulated Mycoplasma infection in rats

Abstract

The acute phase response is implemented by infected hosts in response to exposure to pathogens, including bacteria and viruses. Acute phase responses comprise physiological and behavioural changes, such as fever and a range of “sickness behaviours”, including lethargy and anorexia as well as impairment in learning and memory. Similar to other sickness behaviours, the effect of infection on learning and memory processes has been attributed to the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6). However, the exact role of IL-1β and IL-6 in mediating infection-induced cognitive impairment is not clear. Unlike fever, anorexia and lethargy, which may benefit an infected host, the physiological benefit of cognitive impairment during illness is doubtful. To initiate an acute phase response experimentally, moieties of typical bacteria (Gramnegative and Gram-positive) and viruses frequently are employed. Moieties from the atypical Mycoplasmas seldom have been used. Consequently, there is a dearth of information on the physiological mechanisms that underlie acute phase responses following Mycoplasma infection, despite the prevalence of the disease in the general population. Mycoplasma pneumoniae frequently causes community-acquired pneumonia, which may have serious extra-pulmonary complications, including cognitive deficits. Therefore, I investigated fever and sickness behaviours as well as cytokine responses in simulated, atypical Mycoplasma infection. I implemented an animal model of simulated Mycoplasma infection and characterised fever and sickness behaviours, including lethargy and anorexia as well as impairment in learning and memory during acute and recurrent acute simulated infection. I also characterized the response in the periphery and in the brain of individual pro-inflammatory cytokines, IL-1β and IL-6, to administration of fibroblast-stimulating lipopeptide-1 (FSL-1), which simulates Mycoplasma infection. Using rats, I recorded fever and lethargy with biotelemetry and assessed effects of simulated Mycoplasma infection on learning and memory using a Morris Water Maze. In addition, I examined the histology of tissue from the hippocampus, a key brain area involved in spatial learning and memory, to assess residual effects of simulated Mycoplasma infection on learning and memory. I showed that bolus administration of a pyrogenic moiety from Mycoplasma, fibroblaststimulating lipopeptide-1 (FSL-1), dose-dependently induced fever, lethargy, anorexia and body mass stunting in rats. However, FSL-1 administration did not induce concomitant impairment in spatial learning and memory. Importantly, at the time of testing in the Maze, I found the concentrations of IL-1β to be up-regulated in both the hypothalamus and the hippocampus, while the concentrations of IL-6 were unaffected. I also showed that recurrent acute injections of FSL-1, at 10 d intervals, induced recurrent fevers, lethargy and anorexia without the development of pyrogenic tolerance to any of the sickness responses measured. However, there was no residual body mass stunting in rats and also no growth retardation, despite the recurrent simulated infection. Equally importantly, there were neither lasting detrimental effects on spatial learning and memory nor any residual histological damage to the hippocampus of rats. My findings in simulated Mycoplasma infection are important, firstly because Mycoplasma infection is prevalent in both developing and developed countries and frequently causes outbreaks, and secondly because Mycoplasma infection affects children and adolescents of school-going age. My findings also are encouraging: although lasting detrimental effects, including impairment in learning and memory as well as body mass stunting may occur in other infections, these appear not to be inevitable outcomes in Mycoplasma infection.