Evidence for persistent and cryptic chlamydial infection in the whole animal.

Evidence derives from both experimental and natural chlamydial infections in animals. Thus, infection of the eye of the Taiwan monkey with C. trachomatis in an experimental model of trachoma, leads to intermittent shedding of viable chlamydiae [Wang et al., 1967] similar to that associated with chronic trachoma in humans. In the similar macaque monkey model, chlamydial genetic material (DNA) can be detected in the conjunctivae of the eye in the absence of any shedding of live chlamydiae [Holland et al., 1992], indicating the presence of persisting, cryptic infection. In the mouse, agents which suppress the immune response, such as cyclophosphamide or anti-inflammatory corticosteroid can reactivate cryptic lung [Laitinen et al., 1996] or genital tract infection [Cotter et al., 1997], leading to the renewed shedding of live chlamydiae. These and other data suggest that, in animals with competent immune defences, the immune systems normally severely limit chlamydial replication to localised sites of infection in the eye, lung or genital tract, permitting only intermittent shedding of live chlamydial EB. However severely immunosuppressed mice, or mice lacking the ability to make ifng, suffer severe infection, with prolonged shedding of live chlamydiae and extension of the infection into deep tissues and organs. This is consistent with the theoretical model of the relationship between interferon, cell mediated immunity and chlamydial development already discussed.

Chronic intermittent shedding of either Chlamydophila abortus (ovine abortion agent) or Chlamydophila pecorum is common in natural infection of sheep. Isolates of C. pecorum from chronic infection of the sheep gut frequently spontaneously produce persistent cryptic infection in cell cultures, often failing to produce productive infection and associated inclusions after culture in the laboratory for several weeks [Philips & Clarkson, 1995.

Tryptophan (Trp) catabolism appears to be an important mechanism for regulation of inflammatory responses, resulting in T-cell tolerance and survival of semi-allogeneic products of conception during pregnancy. Trp catabolism can be induced by IFN-gamma, and is therefore an important host defence mechanism against intracellular pathogens. Chlamydophila abortus is a bacterial pathogen that can cause persistent infection in non-pregnant sheep, while in the pregnant ovines it invades the placenta and causes abortion in late pregnancy. IFN-gamma was found to control the growth of _ Chlamydophila abortus_ in ovine cells in a highly dose-dependent manner. Addition of 200U/ml IFN-gamma eradicated all traces of infection from the cultures. Concentrations less than 50U/ml failed to control the growth of the organism, leading to host cell lysis. Intermediate concentrations in the range 50-100U/ml resulted in persistent infection, allowing survival of the organism on passage in tissue culture for several months. Removal of IFN-gamma resulted in the re-appearance of infectious organisms. Addition of exogenous Trp to infected cells treated with 50-100U/ml IFN-gamma prevented the establishment of persistence. These effects in tissue culture are analogous to the persistent infection observed in pregnant sheep prior to abortion. These data suggest that control of Chlamydophila abortus growth in the periphery is linked to the balance of pro-inflammatory cytokine production and the availability of Trp during pregnancy [Brown et al., 2001].

MeWard 2002

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Brown, J., Howie, S. E. & Entrican, G. (2001). A role for tryptophan in immune control of chlamydial abortion in sheep. Veterinary Immunology and Immunopathology 82, 107 - 119.

Cotter, T.W., Miranpuri, G.S., Ramsey, K.H., Poulsen, C.E., and Byrne, G.I. (1997): Reactivation of chlamydial genital tract infection in mice. Infection and Immunity 65, 2067 - 2073.

Holland, S.M., Hudson, A.P., Bobo, L., Whittumhudson, J.A., Viscidi, R.P., Quinn, T.C., and Taylor, H.R. (1992): Demonstration of chlamydial RNA and DNA during a culture negative state. Infection and Immunity 60, 2040 - 2047.

Laitinen, K., Laurila, A.L., Leinonen, M., and Saikku, P. (1996): Reactivation of Chlamydia pneumoniae infection in mice by cortisone treatment. Infection and Immunity 64, 1488 - 1490.

Philips, H.L. and Clarkson, M.J. (1995): Spontaneous change from overt to covert infection of Chlamydia pecorum in cycloheximide treated mouse McCoy cells. Infection and Immunity 63, 3729 - 3730.

Wang, S.P., Grayston, J.T., and Alexander, E.R. (1967). Trachoma vaccine studies in monkeys. American Journal of Ophthalmology 63, 1615 - 1620.

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