Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both orthopoxviruses encode tumor necrosis factor receptor (TNFR) homologs or viral TNFR (vTNFR). These homologs are termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain called smallpox virus-encoded chemokine receptor (SECRET) domain. ECTV encodes one vTNFR known as CrmD. Infection of ECTV-resistant C57BL/6 mice with a CrmD deletion mutant virus resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production. CrmD dampened pathology, leukocyte recruitment, and inflammatory cytokine production in lungs including TNF, IL-6, IL-10, and IFN-γ. Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung pathology and provided 60 to 100% protection from otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were absent. Presence of the SECRET domain alone induced significantly higher levels of IL-1β, IL-6, and IL-10, likely overcoming any protective effects that might have been afforded by anti–IFN-γ treatment. The use of TNF-deficient mice and those that express only membrane-associated but not secreted TNF revealed that CrmD is critically dependent on host TNF for its function. In vitro, recombinant Crm proteins from different orthopoxviruses bound to membrane-associated TNF and dampened inflammatory gene expression through reverse signaling. CrmD does not affect virus replication; however, it provides the host advantage by enabling survival. Host survival would facilitate virus spread, which would also provide an advantage to the virus.

Ectromelia病毒（ECTV）引起了鼠痘，这是由天花病毒引起的天花的替代小鼠模型。两种正痘病毒均编码肿瘤坏死因子受体（TNFR）同源物或病毒TNFR（vTNFR）。这些同源物称为细胞因子反应修饰物（Crm）蛋白，包含TNF结合域和称为天花病毒编码趋化因子受体（SECRET）的趋化因子结合域。ECTV编码一种称为CrmD的vTNFR。用CrmD缺失突变病毒感染ECTV耐药性C57BL / 6小鼠，由于TNF分泌过多和炎性细胞因子产生失调，导致均匀的死亡率。CrmD抑制了包括TNF，IL-6，IL-10和IFN-γ在内的肺部的病理，白细胞募集和炎性细胞因子的产生。TNF，IL-6，单克隆抗体具有IL-10R或IL-10R的功能可减少肺部病理，并提供60至100％的保护，使其免受致命的感染。仅当TNF结合域和SECRET域均缺失时，IFN-γ才引起肺部病理。单独存在SECRET结构域可诱导显着更高的IL-1β，IL-6和IL-10水平，可能克服了抗IFN-γ治疗可能提供的任何保护作用。使用TNF缺陷型小鼠和仅表达膜相关但不分泌TNF的小鼠表明，CrmD的功能严重依赖宿主TNF。在体外，来自不同正痘病毒的重组Crm蛋白与膜相关TNF结合，并通过反向信号减弱炎症基因的表达。CrmD不会影响病毒复制；然而，它通过实现生存来提供主机优势。宿主存活将促进病毒传播，这也将为病毒提供优势。