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Zika stifles pregnant women's immune system
A pregnant woman's weakened immune system enables the virus to spread, increasing the chances an unborn baby will be harmed, a Keck School of Medicine of USC study finds. The study is the first to report that the Zika virus targets specific white blood cells, handicapping a pregnant woman's immune system in a way that almost resembles HIV, said Jae Jung, senior author of the study.
"Pregnant women are more susceptible to Zika virus because pregnancy naturally suppresses a woman's immune system so her body doesn't reject the fetus — essentially it's a foreign object."
Jung: "Our study shows pregnant women are more prone to immune suppression. Zika exploits that weakness to infect and replicate."
The finding, published in Nature Microbiology on Aug. 14. Previously, Jung and his colleagues identified two Zika proteins responsible for microcephaly. It was a first step toward preventing Zika-infected mothers from giving birth to babies with abnormally small heads.
None of the Phase 1 clinical trials for a Zika vaccine included pregnant women, which is surprising because the congenital birth defects caused by the virus is the reason why people are so eager to develop a vaccine, Jung said. Nearly 3,000 cases of microcephaly have been associated with mothers who were infected with the Zika virus before giving birth, according to the Pan American Health Organization.
"The Zika virus vaccines in development seem to be highly effective, but they're being tested among non-pregnant women with different body chemistry compared to pregnant women," Jung explains. "It's feasible the recommended vaccine dose — though effective for non-pregnant women — may not be potent enough for pregnant women because their bodies are more tolerant of viruses."
Jung and his colleagues tested the African and Asian Zika virus strains in blood samples of healthy men, non-pregnant women and pregnant women ages 18 through 39. In one experiment, they infected blood obtained from non-pregnant and pregnant women with both Zika virus strains. The blood samples were then analyzed at peak infection. The virus made a beeline for white blood cells called "CD14+ monocytes" that then turn into macrophages — trash bags that swallow viruses, bacteria and cellular debris to make the body healthy.
The Asian Zika strain pushed these white blood cells to transform into "M2 macrophages" that tell the immune system to power down because the threat is over. The false signal handicaps the immune system and allows the Zika virus to quickly replicate. Notably, pregnant women naturally have higher levels of immune-suppressing M2 macrophages to prevent the womb from rejecting the fetus. However, the Asian Zika virus turbo boosts M2 macrophage reproduction, decreasing the number of infection-killing soldiers and encouraging further immune suppression.
Researchers discovered the Asian Zika virus is more pernicious during a woman's first and second trimester, when the virus can increase immune suppression. During the third trimester, the blood of infected pregnant women and non-pregnant women were about the same. In the study, Zika virus infection of merely 4 percent of the target white blood cells was enough to convert a big population of "white knights" into immune suppressive M2 macrophages. African Zika virus infection increased immune suppression to around 10 percent. This number skyrocketed to almost 70 percent for expectant mothers infected by the Asian Zika virus.
"During pregnancy, the host body is prone to opportunistic infection. With the help of pregnant women's naturally weaker immune system, it's possible for the Asian Zika virus to sneak into the womb and prey on the vulnerable baby."
Previous clinical studies by others showed that Zika virus infection during the first and second trimesters of pregnancy are strongly associated with fetal abnormalities. In the current study, researchers compared their experimental findings with the blood of 30 pregnant patients (10 from each trimester) diagnosed with the Asian Zika virus infection. They also analyzed the blood of 15 pregnant women (about 5 from each trimester) who were not infected.
Patient samples showed abnormally high expression of the genes ADAMTS9 and FN1, which have been associated with pregnancy complications. The former may be responsible for underweight newborns and prolonged or complicated baby delivery. Increased levels of the latter have been associated with womb abnormalities that lead to unusually small babies and pre-eclampsia (high maternal blood pressure).
According to author, Ji Seung Yoo, Phd: "Although microcephaly has gotten a lot of attention, the more widespread problem is deformed brain development and the formation of calcium clumps in the brains of newborns. These anomalies cause brain damage and developmental delays in babies even if they are born with normal-sized heads."
Blood CD14+ monocytes are frontline immunomodulators categorized into classical, intermediate or non-classical subsets, and subsequently differentiated into M1 pro- or M2 anti-inflammatory macrophages on stimulation. Although the Zika virus (ZIKV) rapidly establishes viraemia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by the African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by the Asian-lineage ZIKV infection. Importantly, infection of the blood of pregnant women revealed an enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with a global suppression of type I interferon-signalling pathway and an aberrant expression of host genes associated with pregnancy complications. Also, 30 ZIKV+ sera from symptomatic pregnant patients showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy-complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, on infection with different lineages of ZIKV.
All authors: Suan-Sin Foo, Weiqiang Chen, Yen Chan, James W. Bowman, Lin-Chun Chang, Younho Choi, Ji Seung Yoo, Jianning Ge, Genhong Cheng, Alexandre Bonnin, Karin Nielsen-Saines, Patrícia Brasil & Jae U. Jung
The current finding was a joint effort with Yen Chan in the Keck School's Department of Obstetrics and Gynecology, Alexandre Bonnin at the Zilkha Neurogenetic Institute, Karin Nielsen and Genhong Cheng at the David Geffen School of Medicine at UCLA, and Patricia Brasil at the National Institute of Infection Disease, Fiocruz in Brazil.
The work was supported by $3.86 million from National Institutes of Health grants (CA200422, CA180779, DE023926, AI073099, AI116585) and The Fletcher Jones Foundation.
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The Zika virus as found in neural stem cell which give rise to the brain's cerebral cortex.
These stem cells were found to act as havens for viral reproduction.
Image Credit: Guo-Li Ming Laboratory, Johns Hopkins University, USA