Zika Virus Replication in Myeloid Cells during Acute Infection Is Vital to Viral Dissemination and Pathogenesis in a
Erin M McDonald1, John Anderson2, Jeff Wilusz2
1Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA.
Abstract:
Zika virus (ZIKV) can establish infection in immune privileged sites such as the testes, eye, and placenta. Whether ZIKV infection of white blood cells is required for dissemination of the virus to immune privileged sites has not been definitively shown. To assess whether initial ZIKV replication in myeloid cell populations is critical for dissemination during acute infection, recombinant ZIKVs were generated that could not replicate in these specific cells. ZIKV was cell restricted by insertion of a complementary sequence to a myeloid-specific microRNA in the 3' untranslated region. Following inoculation of a highly sensitive immunodeficient mouse model, crucial immune parameters, such as quantification of leukocyte cell subsets, cytokine and chemokine secretion, and viremia, were assessed. Decreased neutrophil numbers in the spleen were observed during acute infection with myeloid-restricted ZIKV that precluded the generation of viremia and viral dissemination to peripheral organs. Mice inoculated with a nontarget microRNA control ZIKV demonstrated increased expression of key cytokines and chemokines critical for neutrophil and monocyte recruitment and increased neutrophil influx in the spleen. In addition, ZIKV-infected Ly6Chi monocytes were identified in vivo in the spleen. Mice inoculated with myeloid-restricted ZIKV had a decrease in Ly6Chi ZIKV RNA-positive monocytes and a lack of inflammatory cytokine production compared to mice inoculated with control ZIKV.IMPORTANCE Myeloid cells, including monocytes, play a crucial role in immune responses to pathogens. Monocytes have also been implicated as "Trojan horses" during viral infections, carrying infectious virus particles to immune privileged sites and/or to sites protected by physical blood-tissue barriers, such as the blood-testis barrier and the blood-brain barrier. In this study, we found that myeloid cells are crucial to Zika virus (ZIKV) pathogenesis. By engineering ZIKV clones to encode myeloid-specific microRNA target sequences, viral replication was inhibited in myeloid cells by harnessing the RNA interference pathway. Severely immunodeficient mice inoculated with myeloid-restricted ZIKV did not demonstrate clinical signs of disease and survived infection. Furthermore, viral dissemination to peripheral organs was not observed in these mice. Lastly, we identified Ly6Cmid/hi murine monocytes as the major myeloid cell population that disseminates ZIKV.
Insights
Myeloid cells are essential for Zika virus (ZIKV) spread. Restricting ZIKV replication in these cells prevented viremia and organ dissemination in mice, highlighting their role in pathogenesis.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Zika virus (ZIKV) infects immune-privileged sites like the testes and placenta.
- The role of white blood cells, specifically myeloid cells, in ZIKV dissemination to these sites remains unclear.
- Monocytes are suspected
- Trojan horses
- for viral spread to protected anatomical locations.
Purpose of the Study:
- To determine if ZIKV replication in myeloid cells is critical for viral dissemination to immune-privileged sites during acute infection.
- To investigate the role of myeloid cell tropism in ZIKV pathogenesis and immune response.
Main Methods:
- Engineered recombinant ZIKV with myeloid-specific microRNA target sequences to restrict replication in myeloid cells.
- Utilized a highly sensitive immunodeficient mouse model for ZIKV inoculation.
- Assessed immune parameters including leukocyte subsets, cytokine/chemokine profiles, and viral load (viremia and organ dissemination).
Main Results:
- Myeloid-restricted ZIKV significantly reduced neutrophil numbers in the spleen and prevented viremia and dissemination to peripheral organs.
- Control ZIKV led to increased pro-inflammatory cytokines, chemokines, and neutrophil influx in the spleen.
- ZIKV RNA-positive Ly6Chi monocytes were identified as key myeloid cells involved in viral dissemination, and their numbers were reduced with myeloid-restricted ZIKV.
Conclusions:
- Myeloid cells, particularly Ly6Cmid/hi monocytes, are crucial for ZIKV pathogenesis and dissemination.
- Inhibiting ZIKV replication in myeloid cells via RNA interference effectively prevents systemic spread and disease.
- This study demonstrates the critical role of myeloid cell tropism in ZIKV's ability to reach immune-privileged sites.
