ANTIBODY AND CYTOKINE RESPONSES IN A MOUSE PULMONARY MODEL OF SHIGELLA-FLEXNERI SEROTYPE 2A INFECTION

A murine pulmonary model was used to study the mucosal immune response to Shigella flexneri serotype 2a infection. Inoculation of BALB/cJ mi ce with shigellae via the intranasal route resulted in bacterial invas ion of bronchial and alveolar epithelia with concomitant development o f acute suppurative bronchiolitis and subsequent development of lethal pneumonia. The pathology of pulmonary lesions resembled the colitis t hat characterizes shigellosis in humans and primates. Significant prot ection against a lethal dose of S. flexneri 2a was observed in mice pr eviously infected with two sublethal doses of the homologous strain. I mmunity against lethal challenge was associated with decreased bacteri al invasion of the mucosal epithelium. Over the course of two subletha l challenges, which constituted primary and secondary immunizations, m ice developed pulmonary and serum immunoglobulin G and A antibody reco gnizing both lipopolysaccharide and invasion plasmid antigens IpaB and IpaC. Immune mice and naive control mice differed in lung lavage cyto kine levels following lethal challenge. Immune mice developed signific antly elevated levels of pulmonary gamma interferon within 6 h of chal lenge, while naive control mice developed elevated levels of this cyto kine later during the initial 24-h period. Both groups had elevated le vels of gamma interferon during the 24- to 48-h period of infection. B oth groups also had elevated levels of tumor necrosis factor alpha wit hin 6 h of challenge, but the control mice had significantly higher le vels at the 48- and 72-h time points. Elevated levels of interleukin-i l were observed only in immunized mice. This cytokine appeared within 24 h and receded between 48 and 72 h. Fluorescence-activated cell sort er analysis of lung parenchymal cells showed that both groups experien ced an initial influx of monocytes, but the proportion of this cell ty pe began to recede in immunized mice after 48 h of infection, while pe ak levels were maintained in the control animals. These studies sugges t that elements of local B lymphocyte activity, as well as Th-1 and Th -2 lymphocyte activity, may contribute to the survival of immune mice after intranasal challenge with shigellae.