Late production of CXCL8 in ruminant oro-nasal turbinate cells in response to Chlamydia abortus infection
Article, Doctoral thesis
Wattegedera, S R
Glass, E J
- Publisher: The University of Edinburgh
cytokine | PRR | Chlamydia abortus | inflammasome | pathogen recognition | pattern recognition receptor
mesheuropmc: animal diseases
Chlamydia abortus is the most common known infectious cause of ovine abortion
worldwide but is rarely linked with bovine abortion. The reasons for this differential
pathogenesis are unknown but may involve differences in innate immune recognition
and immune responsiveness. This is supported by the observation that chlamydial
abortion in sheep is associated with an inflammatory cytokine/chemokine cascade
that is not commonly observed in cattle. Studies with other Chlamydia species have
demonstrated that innate inflammatory pathways including inflammasome activation
contribute to both pathogen clearance and pathology. Pattern recognition receptors
(PRRs) activate these innate immune signalling pathways but are relatively poorly
characterized in ruminants. We hypothesize that the ruminant hosts differ in their
ability to innately sense C. abortus infection and activate the inflammasome. The
main aims of this project were to: analyse PRR expression in innate immune cells;
assess cytokine production from innate immune cells in response to C. abortus;
investigate the role of PRRs in the induction of innate immune responses to C.
abortus; and, conduct RNA-seq analysis on macrophages following infection with C.
abortus to identify important immune signalling pathways.
Ruminant oro-nasal turbinate cells, monocyte derived dendritic cells (MDDCs) and
monocyte derived macrophages (MDMs) express the cell-surface PRRs TLR2 and
TLR4 and also the intracellular PRRs NOD 1 and NLRP3. Oro-nasal turbinate cells
produce CXCL8 late into the chlamydial developmental cycle independent of IL-1β.
In contrast, ruminant MDMs and MDDCs secrete early IL-1β in response to C.
abortus infection. In MDMs and MDDCs, live and UV-inactivated C. abortus
induced TNF-α and CXCL8 but live infection was required for IL-1β secretion.
Therefore, intracellular C. abortus multiplication is necessary to stimulate the IL-1β
processing pathway within these cells. In order to determine PRR function, NOD1
and NLRP3 were knocked down in ruminant MDMs using siRNA. In both ovine and
bovine MDMs, NOD1 was identified as a factor in C. abortus mediated IL-1β
production. NLRP3 knockdown in bovine but not ovine MDMs also reduced IL-1β
production, indicating species-specific differences in C. abortus recognition. The
RNA-seq analysis of ruminant MDMs identified novel pathways of immune
activation by C. abortus and potentially important species-specific differences. An
improved understanding of the innate immune pathways activated in susceptible and
resistant hosts following C. abortus infection will inform on disease pathogenesis
and could contribute to novel chlamydial vaccine design.
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