Host cytokines and immune responses in pregnancy associated transmission of arrested hookworm larvae
TRIVEDI, SHWETA. Host cytokines and immune responses in pregnancy associated transmission of arrested hookworm larvae (Under the direction of Dr. Prema Arasu)
Over one billion people worldwide are infected with blood-feeding intestinal hookworms. The life cycle of A. duodenale (humans) and A. caninum (dogs) includes the propensity for L3 to undergo a temporary state of developmental arrest in the host. In female hosts, tissue-arrested L3 reactivate during pregnancy and are transmitted to neonates through milk. During pregnancy, transforming growth factor (TGF)-â2 is upregulated in the mammary gland. Studies in C. elegans show that TGF-â and insulin-like signaling pathways regulate larval arrest and reactivation. We previously utilized an in vitro assay to demonstrate that recombinant human TGF-â stimulates a feeding response in tissue-arrested A. caninum L3. We hypothesize that host expression of TGF-â and pregnancy hormones such as estrogen and prolactin signal arrested L3 to reactivate.
To facilitate in vivo analyses, we utilized a mouse model of A. caninum infection. Mice were utilized because L3 do not develop into adults but arrest in somatic tissues, and reactivate during the periparturient period. We investigated TGF-â1, TGF-â2 and IGF-1 transcript and serum cytokine profiles during late pregnancy, early lactation and mid-lactation to correlate levels with transmammary transmission of L3 to nursing pups. An in vitro co-culture system was developed to mimic in vivo conditions and assess effects of TGF-â and, estrogen and prolactin on larval reactivation. A. caninum L3 were co-incubated with skeletal muscle or mammary epithelial cells and larval reactivation was measured. Additionally, immune responses were assessed as by measuring serum and transcript levels of IFN-ã and IL-4 in skeletal muscle, mammary gland and spleen to dissect the effects of pregnancy and A. caninum infection in the mouse.
Our findings suggest that host-derived TGF- â1 and IGF-1, but not TGF- â2, are important in reactivation and transmission of arrested A. caninum larvae. Also, a Th2-like response characterized by increased IL-4 transcript levels was observed in skeletal muscle, while a mixed Th1/Th2 profile was observed in mammary gland when comparing infection with A. caninum versus pregnancy/lactation in BALB/c mice.
Advisor:Prema Arasu; William Miller; Paul Mozdziak; Scott Laster
School:North Carolina State University
School Location:USA - North Carolina
Source Type:Master's Thesis
Date of Publication:09/30/2005