December 1, 2023

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Monkeypox Initial Infection Provides Protection Against Secondary Infection

Monkeypox Initial Infection Provides Protection Against Secondary Infection


Monkeypox Initial Infection Provides Protection Against Secondary Infection.

The monkeypox outbreak that occurred between 2022 and 2023 affected over 80,000 cases across 110 countries worldwide, with approximately 30,000 cases reported in the United States.

This outbreak was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO).

The monkeypox epidemic spread rapidly on a global scale and exhibited unique clinical manifestations, with a primary focus on cases among men who have sex with men (MSM).

The virus strain responsible for this outbreak was identified as the 2b branch of the West African B.1 lineage. However, much remains unknown about the pathogenesis and immune mechanisms of this monkeypox outbreak.

On September 20, 2023, a research team led by Dan H. Barouch from the Harvard Medical School and Beth Israel Deaconess Medical Center in the United States published a study in Cell titled “Mpox infection protects against re-challenge in rhesus macaques,” using rhesus macaques as a model to study monkeypox virus infection. They discovered that three different routes of monkeypox infection can trigger robust natural immunity, providing protection against secondary monkeypox infection, with adaptive immune responses playing a crucial role.


Monkeypox Initial Infection Provides Protection Against Secondary Infection



The researchers initially inoculated 18 adult rhesus macaques with monkeypox virus using three different injection methods: intravenous (i.v.), subcutaneous (i.d.), and rectal (i.r.) injections. They evaluated humoral and cellular immune responses at 14 and 28 days post-inoculation. At 14 days post-inoculation, all 18 rhesus macaques exhibited binding antibody responses to monkeypox virus (MPXV), and at 28 days post-inoculation, neutralizing antibody responses were detected in all groups except the low-dose intravenous injection group. CD8+ and CD4+ cell responses were also detected in all rhesus macaques at 28 days post-inoculation.


They assessed clinical symptoms by counting pox lesions on the skin at days 0, 3, 7, 10, 14, 21, and 28 post-inoculation. Skin pustules were observed on day 7, peaked between days 10 and 14, and appeared on various body parts including the limbs, head, face, neck, chest, abdomen, back, groin, and tail. The severity of clinical symptoms depended on the inoculation dose and method, with the rectal injection group showing the fewest skin lesions.

One rhesus macaque in the subcutaneous injection group at a dose of 106 TCID50 experienced a weight loss exceeding 20% on day 21, reaching euthanasia criteria. All animals, however, recovered from skin lesions by day 28. Plasma virus DNA load peaked on day 10 for intravenous injection and day 7 for subcutaneous and rectal injections, with viral load dependent on the injection dose and method. Viral load was cleared in all groups by days 14-28 post-inoculation.


After 28 days following the initial inoculation, the researchers performed a secondary intravenous injection of monkeypox virus on all 18 previously inoculated rhesus macaques and 3 non-inoculated ones. The secondary infection group exhibited resistance to virus infection, with no skin lesions observed. One day after secondary inoculation, eight out of 17 rhesus macaques had detectable baseline levels of viral load in their plasma, but it became undetectable thereafter.

Furthermore, post-mortem examinations revealed extensive skin vesicles and ulcerations in the epidermis, characterized by epidermal hyperkeratosis, intracytoplasmic Guanieri-like bodies, lymphohistiocytic and neutrophilic dermatitis with necrosis, and syncytial and ballooning degeneration, with the presence of virus detected in skin lesions.


To investigate the pathogenesis and immune mechanisms of monkeypox infection, transcriptome analysis was conducted on peripheral blood samples collected at days 0, 1, 3, 7, 14, 21, and 28 post-initial inoculation and days 1, 3, 7, and 10 post-secondary inoculation. The study revealed that innate immune cell signatures, cytokine and chemokine signaling, IFN, and inflammatory responses were upregulated on day 1 post-inoculation and returned to baseline levels by days 7-14. Activation of these pathways significantly decreased after secondary inoculation.

T cell activation and differentiation gene signatures were significantly upregulated on day 7 post-initial inoculation, while B cells and plasma cells increased on day 14 post-initial inoculation, with T cell and plasma cell pathways activated by day 3 post-secondary inoculation. Moreover, pathways related to cell motility and adhesion, collagen formation, tissue repair, extracellular matrix assembly, and metabolism were significantly downregulated, indicating disruption of skin barrier and cellular metabolic dysregulation due to monkeypox infection.


Monkeypox Initial Infection Provides Protection Against Secondary Infection



In summary, this study, using rhesus macaques as a model, reveals that monkeypox virus infection through three different routes can induce protective immune responses against secondary infection, laying the foundation for further research on combating monkeypox outbreaks.





Monkeypox Initial Infection Provides Protection Against Secondary Infection

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