Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile

doi:10.3390/pathogens8040223

. 2019 Nov 7;8(4):223.

doi: 10.3390/pathogens8040223.

Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile

Priscila Conrado Guerra Nunes¹, Lilimar da Silveira Rioja², Janice Mery Chicarino de Oliveira Coelho³, Natália Gedeão Salomão⁴, Kíssila Rabelo⁵, Carollina Ceia José⁴, Francisco das Chagas de Carvalho Rodrigues³, Elzinandes Leal de Azeredo¹, Carlos Alberto Basílio-de-Oliveira⁶, Rodrigo Basílio-de-Oliveira⁶, Rita Maria Ribeiro Nogueira⁷, Juan Camilo Sánchez-Arcila⁸, Flávia Barreto Dos Santos¹, Marciano Viana Paes⁴

Affiliations

¹ Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro-RJ 21040900, Brazil.
² Departamento de Patologia e Laboratórios, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro-RJ 20550170, Brazil.
³ Laboratório de Anatomia Patológica, Instituto Nacional de Infectologia, Fundação Oswaldo Cruz /FIOCRUZ, Rio de Janeiro-RJ 21040900, Brazil.
⁴ Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz /FIOCRUZ, Rio de Janeiro-RJ 21040900, Brazil.
⁵ Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro/UERJ, Rio de Janeiro- RJ 20550170, Brazil.
⁶ Anatomia Patológica, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro-RJ 20270004, Brazil.
⁷ Laboratório de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz /FIOCRUZ Rio de Janeiro-RJ 21040900, Brazil.
⁸ School of Natural Sciences, University of California, Merced-CA 95343, USA.

PMID: 31703246
PMCID: PMC6963280
DOI: 10.3390/pathogens8040223

Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile

Priscila Conrado Guerra Nunes et al. Pathogens. 2019.

. 2019 Nov 7;8(4):223.

doi: 10.3390/pathogens8040223.

Authors

Affiliations

¹ Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro-RJ 21040900, Brazil.
² Departamento de Patologia e Laboratórios, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro-RJ 20550170, Brazil.
³ Laboratório de Anatomia Patológica, Instituto Nacional de Infectologia, Fundação Oswaldo Cruz /FIOCRUZ, Rio de Janeiro-RJ 21040900, Brazil.
⁴ Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz /FIOCRUZ, Rio de Janeiro-RJ 21040900, Brazil.
⁵ Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro/UERJ, Rio de Janeiro- RJ 20550170, Brazil.
⁶ Anatomia Patológica, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro-RJ 20270004, Brazil.
⁷ Laboratório de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz /FIOCRUZ Rio de Janeiro-RJ 21040900, Brazil.
⁸ School of Natural Sciences, University of California, Merced-CA 95343, USA.

PMID: 31703246
PMCID: PMC6963280
DOI: 10.3390/pathogens8040223

Abstract

Dengue virus (DENV) infections may result in asymptomatic cases or evolve into a severe disease, which involves multiple organ failure. Renal involvement in dengue can be potentially related to an increased mortality. Aiming to better understand the role of DENV in renal injury observed in human fatal cases, post-mortem investigations were performed in four DENV-4 renal autopsies during dengue epidemics in Brazil. Tissues were submitted to histopathology, immunohistochemistry, viral quantification, and characterization of cytokines and inflammatory mediators. Probably due the high viral load, several lesions were observed in the renal tissue, such as diffuse mononuclear infiltration around the glomerulus in the cortical region and in the medullary vessels, hyalinosis arteriolar, lymphocytic infiltrate, increased capsular fibrosis, proximal convoluted tubule (PCT) damage, edema, PCT debris formation, and thickening of the basal vessel membrane. These changes were associated with DENV-4 infection, as confirmed by the presence of DENV-specific NS3 protein, indicative of viral replication. The exacerbated presence of mononuclear cells at several renal tissue sites culminated in the secretion of proinflammatory cytokines and chemokines. Moreover, it can be suggested that the renal tissue injury observed here may have been due to the combination of both high viral load and exacerbated host immune response.

Keywords: cytokines; dengue 4; fatal case; histopathology; inflammatory mediators; viremia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Renal histological analysis. (A) Non-dengue control evidencing cortical region with the presence of renal glomerulus (GR) and proximal contiguous tubules (PCT) and distal tubules (DCT). (B) Dengue case showing the presence of inflammatory infiltrate (Ly), hyalinoses (Hy) arteriole (a), vascular congestion (VC) in the renal glomerulus (RG), thickened Bowman’s capsule (BC) and damage (star) PCT. (C) Dengue case showing tubular debris (D), edema (E), and pockets of hemorrhage (He). (D) Presence of hyalinoses (Hy) arteriole (a) and damage (star) PCT in the dengue case. (E) Glomerular and peri-glomerular vascular (VC) congestion, presence of Bowman’s capsule (BC), and damage (star) PCT in the case of dengue stained with Masson. (F) Peritubular lymphocyte infiltrate (Ly), Bowman’s capsule (BC), damage (star) PCT, and preserved DCT in dengue case stained with Periodic acid-Schiff reaction (PAS). (G) Lymphocyte infiltrates (Inf) inside the capillary loops around the proximal convoluted tubules in the cortical region of dengue fatal cases. (H) Mononuclear infiltrates (Inf) and vascular congestion (VC) around collecting tubes in the medullar region of dengue fatal cases.

**Figure 2**
Median quantification of renal damage in four dengue fatal cases (n = 4) compared to control cases (n = 4). (A) Vascular congestion in renal cortical regions (*p = 0.0040*). (B) Tubular degeneration (p ≤ *0.0001*). (C) Renal cortical infiltrates (p ≤ *0.0001*). (D) Vascular congestion in renal medullary regions (*p = 0.1280*). (E) Tubular necrosis (*p = 0.0008*). (F) Infiltrates in renal medullary regions (p ≤ *0.0001*).

**Figure 3**
Immunohistochemistry of viral staining, subpopulations, and cytokines/chemokines: (A) Non-dengue case control without dengue virus (DENV) NS3 staining. (B,C) Detection of DENV NS3 in the dengue case within macrophages (Mø), Mesenchymal cells (MC), endothelial cells (En) in the cortical region, and macrophages (Mø) in the medullar region. (D) Control with CD68 staining inside the glomerulus. (E,F) Expression of CD68-labeled cells in the cortical and medullary regions of the dengue case. (G) Control with CD8⁺ peritubular staining. (H,I) Expression of CD8⁺ T cells in the medullary and cortical region of the DENV-4 case. (J) Representative negative control of cytokine and inflammatory mediators. (K) DENV-4 case with mononuclear infiltrate (Inf) expressing TNF-α, macrophages (Mø) expressing MCP-1 (L), and macrophages (Mø) expressing VEGF/R2 (M). Cells showing double staining (green and red) were observed in control (N) and fatal dengue cases (O).

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[1] Kuhn R.J., Zhang W., Rossmann M.G., Pletnev S.V., Corver J., Lenches E., Jones C.T., Mukhopadhyay S., Chipman P.R., Strauss E.G., et al. Structure of dengue virus: Implications for flavivirus organization, maturation, and fusion. Cell. 2002;108:717–725. doi: 10.1016/S0092-8674(02)00660-8. - DOI - PMC - PubMed

[2] Kuhn R.J., Zhang W., Rossmann M.G., Pletnev S.V., Corver J., Lenches E., Jones C.T., Mukhopadhyay S., Chipman P.R., Strauss E.G., et al. Structure of dengue virus: Implications for flavivirus organization, maturation, and fusion. Cell. 2002;108:717–725. doi: 10.1016/S0092-8674(02)00660-8. - DOI - PMC - PubMed

[3] Vasilakis N., Cardosa J., Hanley K.A., Holmes E.C., Weaver S.C. Fever from the forest: Prospects for the continued emergence of sylvatic dengue virus and its impact on public health. Nat. Rev. Microbiol. 2011;9:532–541. doi: 10.1038/nrmicro2595. - DOI - PMC - PubMed

[4] Vasilakis N., Cardosa J., Hanley K.A., Holmes E.C., Weaver S.C. Fever from the forest: Prospects for the continued emergence of sylvatic dengue virus and its impact on public health. Nat. Rev. Microbiol. 2011;9:532–541. doi: 10.1038/nrmicro2595. - DOI - PMC - PubMed

[5] Modis Y., Ogata S., Clements D., Harrison S.C. Structure of the dengue virus envelope protein after membrane fusion. Nature. 2004;427:313–319. doi: 10.1038/nature02165. - DOI - PubMed

[6] Modis Y., Ogata S., Clements D., Harrison S.C. Structure of the dengue virus envelope protein after membrane fusion. Nature. 2004;427:313–319. doi: 10.1038/nature02165. - DOI - PubMed

[7] Acosta E.G., Kumar A., Bartenschlager R. Revisiting dengue virus-host cell interaction: New insights into molecular and cellular virology. Adv. Virus Res. 2014;88:1–109. - PubMed

[8] Acosta E.G., Kumar A., Bartenschlager R. Revisiting dengue virus-host cell interaction: New insights into molecular and cellular virology. Adv. Virus Res. 2014;88:1–109. - PubMed

[9] Cruz-Oliveira C., Freire J.M., Conceição T.M., Higa L.M., Castanho M.A.R.B., Da Poian A.T. Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol. Rev. 2015;39:155–170. doi: 10.1093/femsre/fuu004. - DOI - PubMed

[10] Cruz-Oliveira C., Freire J.M., Conceição T.M., Higa L.M., Castanho M.A.R.B., Da Poian A.T. Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol. Rev. 2015;39:155–170. doi: 10.1093/femsre/fuu004. - DOI - PubMed

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Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile

Affiliations

Renal Injury in DENV-4 Fatal Cases: Viremia, Immune Response and Cytokine Profile

Authors

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Abstract

Conflict of interest statement

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References

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Abstract

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