Viral infection, proliferation, and hyperplasia of Hofbauer cells and absence of inflammation characterize the placental pathology of fetuses with congenital Zika virus infection

Abstract

Purpose: Attention is increasingly focused on the potential mechanism(s) for Zika virus infection to be transmitted from an infected mother to her fetus. This communication addresses current evidence for the role of the placenta in vertical transmission of the Zika virus.

Methods: Placentas from second and third trimester fetuses with confirmed intrauterine Zika virus infection were examined with routine staining to determine the spectrum of pathologic changes. In addition, immunohistochemical staining for macrophages and nuclear proliferation antigens was performed. Viral localization was identified using RNA hybridization. These observations were combined with the recent published results of placental pathology to increase the strength of the pathology data. Results were correlated with published data from experimental studies of Zika virus infection in placental cells and chorionic villous explants.

Results: Placentas from fetuses with congenital Zika virus infection are concordant in not having viral-induced placental inflammation. Special stains reveal proliferation and prominent hyperplasia of placental stromal macrophages, termed Hofbauer cells, in the chorionic villi of infected placentas. Zika virus infection is present in Hofbauer cells from second and third trimester placentas. Experimental studies and placentae from infected fetuses reveal that the spectrum of placental cell types infected with the Zika virus is broader during the first trimester than later in gestation.

Conclusions: Inflammatory abnormalities of the placenta are not a component of vertical transmission of the Zika virus. The major placental response in second and third trimester transplacental Zika virus infection is proliferation and hyperplasia of Hofbauer cells, which also demonstrate viral infection.

Keywords: Infection; Microcephaly; Pathology; Placenta; Virus; Zika.

Fig. 1

Appearance of chorionic villi from a stillborn infant at 32 weeks gestation with congenital Zika syndrome including microcephaly. The villi are greatly enlarged for gestational age and are hypercellular, but there is no villitis or necrosis. Most of the stromal cells are macrophages, termed Hofbauer cells. Hematoxylin and eosin stain

Fig. 2

Proliferation of Hofbauer cells in a 21 week gestation Zika virus-infected placenta is evident by the nuclear staining of these macrophages using Ki67 (arrows), an antibody to a nuclear protein strictly associated with cellular proliferation. At the surface of the villus, occasional trophoblast cells (arrowheads) are also in the proliferation phase of the cell cycle

Fig. 3

Chorionic villi from an uninfected placenta at the same gestational age (21 weeks) and magnification as shown in Fig. 4 using an antibody to macrophages, illustrating the normal number of Hofbauer cells (arrows) in the villous stroma

Fig. 4

Abnormally increased numbers of Hofbauer cells can be identified in this enlarged chorionic villus from a 21 week gestation fetus using immunohistochemistry with CD-163 antibody. All the brown-staining cells in this image represent the nuclei villous stromal macrophages (Hofbauer cells). The fetus had microcephaly and Zika virus infection confirmed by RT-PCR

Fig. 5

Higher magnification of Hofbauer cell hyperplasia in the terminal chorionic villi of a placenta from a 21 week gestation infant with intrauterine Zika virus transplacental infection and microcephaly. CD163 antibody. All the brown-staining structures (arrows) are nuclei of Hofbauer cells, which are tightly packed in the villous stroma. The trophoblastic outer layer (arrowheads) of the villi stains blue

Fig. 6

Zika virus RNA (red arrow) is positive in a stromal cell, presumably a Hofbauer cell, in the chorionic villus of the placenta of a 21 week gestational age fetus with congenital Zika virus infection and microcephaly. RNAscope