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. 2021 Aug 9;13(8):1571.
doi: 10.3390/v13081571.

Acute Late-Stage Myocarditis in the Crab-Eating Macaque Model of Hemorrhagic Smallpox

Reed F Johnson  1   2 , Lauren A Keith  2 , Timothy K Cooper  2 , Srikanth Yellayi  2 , Nicole M Josleyn  2 , Krisztina B Janosko  2 , James D Pettitt  2 , David Thomasson  2 , Katie R Hagen  2 , Robin Gross  2 , John G Bernbaum  2 , Debbie Douglas  2 , Jeffrey Solomon  3 , Mark Martinez  2 , Kurt Cooper  2 , Marisa St Claire  2 , Danny R Ragland  2 , Peter B Jahrling  1   2 , Jens H Kuhn  2 , Andrew E Arai  4
Affiliations

Acute Late-Stage Myocarditis in the Crab-Eating Macaque Model of Hemorrhagic Smallpox

Reed F Johnson et al. Viruses. .

Abstract

Hemorrhagic smallpox, caused by variola virus (VARV), was a rare but nearly 100% lethal human disease manifestation. Hemorrhagic smallpox is frequently characterized by secondary bacterial infection, coagulopathy, and myocardial and subendocardial hemorrhages. Previous experiments have demonstrated that intravenous (IV) cowpox virus (CPXV) exposure of macaques mimics human hemorrhagic smallpox. The goal of this experiment was to further understand the onset, nature, and severity of cardiac pathology and how it may contribute to disease. The findings support an acute late-stage myocarditis with lymphohistiocytic infiltrates in the CPXV model of hemorrhagic smallpox.

Keywords: CPXV; VARV; biodefense; cardiac MRI; cowpox; myocarditis; smallpox; variola.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services (HHS) or of the institutions and companies affiliated with the authors. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

Figures

Figure 1
Figure 1
Experimental design. BL = baseline sampling, time points prior to intravenous (IV) cowpox virus (CPXV) exposure. PE = physical exam, cMR = cardiac magnetic resonance.
Figure 2
Figure 2
Viremia and tissue virus loads indicate early infection of the bone marrow and spleen. (A) Viremia was observed at Day 5 post-exposure. (B) Tissue viral load suggests early infection of the spleen and bone marrow. BL = baseline sampling, time points prior to intravenous (IV) cowpox virus (CPXV) exposure. Bars indicate standard deviation. Day 0 is not included on the graphs because no measurements were made.
Figure 3
Figure 3
Clinical pathology supports inflammatory response. Total leukocyte (A), monocyte (B), lymphocyte (C), and neutrophil (D) number changes indicate inflammation. BL = baseline sampling, time points prior to intravenous (IV) cowpox virus (CPXV) exposure. Error bars reperesent standard deviation. Day 0 is not included on the graphs because no measurements were made.
Figure 4
Figure 4
Cowpox virus (CPXV) directly infects cardiac tissue. (A,B) Gross pathology image of a fresh, normal heart and formalin-fixed and transversely sectioned normal heart tissue (control group macaques). (C,D) Petechiae and areas of hemorrhage and necrosis (Group 3 macaques). (E,F) Normal control group and Group 3 ventricular myocardium section with florid inflammation. (G) Higher magnification of F showing intracytoplasmic inclusion bodies and inflammatory infiltrate. (H) CPXV antigen (brown) in cardiac fibroblasts. (I) Histopathology scoring. (J,K) Normal control group and Group 3 myocardium. Asterisk: mitochondrial crystolysis; arrows: CPXV particles in cardiac fibroblast. (L–P) Creatine kinase (CK), CK myocardial band (CK MB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and hemolysis over time. BL = baseline sampling, time points prior to intravenous (IV) CPXV exposure. Day 0 is not included on the graphs because no measurements were made.
Figure 5
Figure 5
Myocardial hemorrhage and lymphohistiocytic inflammation in cowpox-virus-exposed macaques does not severely impact heart function. (Baseline values were averaged to establish a mean and one standard deviation left ventricular ejection fraction [LVEF] normal range.) (A) Changes in LVEF. (B) Myocardial hemorrhage as measured by T2*. (C) T2* maps of the most severely affected macaque. White square: area with increased T2*, indicating hemorrhage. (D) Peripheral blood mononuclear cells (PBMCs) infiltrated the heart tissue and peak at Day 6 post-exposure. (E) Circulating PBMC numbers increased by Day 4. Monocyte numbers declined in circulation by Day 7 but remained constant within the myocardium. (F,G) Heart tissue and plasma cytokine concentrations increased as disease progressed. Day 0 is not included on the graphs because no measurements were made.
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