Impaired monocyte-macrophage functions and defective Toll-like receptor signaling in hepatitis E virus-infected pregnant women with acute liver failure.
Acute viral hepatitis resulting due to hepatitis E viral infection (AVH-E) is often serious in pregnancy and could result in acute liver failure (ALF). The role of monocytes and macrophages (mono-macs) in the pathogenesis of AVH-E and development of ALF-E in pregnancy is unclear. We investigated the functions of mono-macs in pregnant (P), AVH-E (n = 44), ALF-E (n = 12), healthy controls (HC; n = 20) and compared with nonpregnant (NP) AVH-E (n = 10), ALF-E (n = 5), and HC (n = 10). We also recruited non-hepatitis E virus-related pregnant (P), ALF-NE (n = 5) and non-pregnant (NP), ALF-NE (n = 12) patients with ALF. Mono-macs, dendritic cell (DC) phenotypes, and Toll-like receptor (TLR) expressions were studied by flow cytometry and reverse-transcriptase polymerase chain reaction. Mono-macs functionality was determined by analyzing their phagocytic activity and reactive oxygen species (ROS) generation by using flow cytometry. Frequency of mono-macs and DCs was increased during HEV infection compared to HC (P < 0.001). Macrophages were increased (P < 0.002) in ALF-E(P) compared to ALF-NE(P). The macrophage phagocytic activity and Escherichia coli-induced ROS production was significantly impaired in ALF-E(P) compared to AVH-E(P) (P < 0.001), ALF-E(NP), and ALF-NE(P) patients (P < 0.02). TLR3 and TLR9 expression and downstream MYD88 signalling molecules IRF3 and IRF7 were significantly down-regulated in ALF-E(P) (P < 0.00) compared to AVH-E(P) and ALF-NE(P).


CONCLUSIONS
Functionality of mono-macs is impaired in pregnant ALF-E patients compared to AVH-E(P). Reduced TLR3 and TLR7 expression and TLR downstream-signaling molecules in pregnant ALF-E patients suggests inadequate triggers for the innate immune responses contributing to development and severity of ALF-E. Studies using TLR agonists to activate mono-macs may be of use and in vitro studies should be undertaken using patient samples.
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Rashi
R
Sehgal
Gynecology and Obstetrics, Lady Harding Medical College, New Delhi, India.
Sharda
S
Patra
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Paul
P
David
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Ashish
A
Vyas
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Arshi
A
Khanam
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Syed
S
Hissar
Department of Virology, Institute of Liver and Biliary Sciences, New Delhi, India.
Ekta
E
Gupta
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Guresh
G
Kumar
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Shyam
S
Kottilil
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Rakhi
R
Maiwall
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.|Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Shiv Kumar
SK
Sarin
Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Nirupama
N
Trehanpati
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D016751:Hepatitis E / Q000097:blood / Q000150:complications* / Q000276:immunology*; D006801:Humans; D017114:Liver Failure, Acute / Q000097:blood / Q000150:complications*; D008264:Macrophages / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000097:blood / Q000276:immunology*; D011446:Prospective Studies; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000502:physiology*; D055815:Young Adult
D051193:Toll-Like Receptors