to 5 years; this variation of duration depends on the host immunity as lesions tend to be more widespread, larger in size, found in atypical areas, and refractory to treatment in immunosuppressed individuals.3,8,16–18,19
Variola virus promotes a robust immune response, potentially causing multi-systemic reactions with a high risk of mortality. Cowpox virus triggers focal cutaneous changes without systemic involvement.20 MCV survives within human skin for a prolonged period without significant immune reaction despite high viral load.13 Partial explanation is that MCV forms a lesion surrounded by keratinocytes that is undetectable by the immune system.13 Additionally, it is hypothesized that MCV evolved complex mechanisms to evade host immune monitoring, thus allowing lesions to persist. We conducted a comprehensive literature review in an effort to better understand the mechanisms underlying MC persistence and immune evasion characteristics of the MCV. This information is essential to understanding the pathogenesis of MC and sparking future investigation of effective treatment options.
MATERIALS AND METHODS
A literature search was conducted at Pubmed, Google Scholar, and Medline, with the keywords of "molluscum contagiosum", "immune evasion", "NF-κB", "chemokines", "viral proteins", and "apoptosis".
RESULTS
Searching "molluscum contagiosum" and various combinations of the search terms above yielded approximately 350 results. Four reviewers participated in the review process and agreed that only articles published in English after 1995 and proposed detailed descriptions of viral proteins and mechanisms of immune invasion were considered. We included 18 original research articles and 4 review articles.
TLR/TNF-induced NF-κB Activation
The human innate and adaptive immune responses coordinate and communicate via various activating and suppressing cytokines and pathways.21 One of the most studied pathways is the nuclear factor-κB (NF-κB) pathway in macrophages. Innate immune cells, such as macrophages, express a plethora of pattern recognition receptor (PRR) that sense the pathogenassociated molecular patterns (PAMPs) which are the essential components of microorganisms.22 Toll like receptors (TLRs) are a distinct class of PRRs present on macrophages and dendritic cells. TLRs encompass 10 variants (TLR-1 through TLR-10) in the human immune system.23
MCV is usually detected by TLR-3 and TLR-9.24 A downstream effect of PRR is the activation of the NF-κB pathway. IκBβ- NF-κB resides in the cytoplasm as an inactive complex; upon phosphorylation induced, proteasome mediated degradation of IκBβ, the NF-κB pathway becomes activated with NF-κB, migrating to the nucleus where it serves as a transcription factor. There, it upregulates the production of inflammatory cytokines and chemokines (Figure 3).22 Tissue necrosis factor (TNF) is also able to trigger NF-κB activation via a similar pathway.25 Activation of NF-κB is required for virus detection, antiviral signaling, inflammation, and clearance of viral infections.26
Although the understanding of MCV is incomplete, several MC proteins have been identified as pivotal host immunomodulators. MC005 protein inhibits NF-κB by binding
TLR/TNF-induced NF-κB Activation
The human innate and adaptive immune responses coordinate and communicate via various activating and suppressing cytokines and pathways.21 One of the most studied pathways is the nuclear factor-κB (NF-κB) pathway in macrophages. Innate immune cells, such as macrophages, express a plethora of pattern recognition receptor (PRR) that sense the pathogenassociated molecular patterns (PAMPs) which are the essential components of microorganisms.22 Toll like receptors (TLRs) are a distinct class of PRRs present on macrophages and dendritic cells. TLRs encompass 10 variants (TLR-1 through TLR-10) in the human immune system.23
MCV is usually detected by TLR-3 and TLR-9.24 A downstream effect of PRR is the activation of the NF-κB pathway. IκBβ- NF-κB resides in the cytoplasm as an inactive complex; upon phosphorylation induced, proteasome mediated degradation of IκBβ, the NF-κB pathway becomes activated with NF-κB, migrating to the nucleus where it serves as a transcription factor. There, it upregulates the production of inflammatory cytokines and chemokines (Figure 3).22 Tissue necrosis factor (TNF) is also able to trigger NF-κB activation via a similar pathway.25 Activation of NF-κB is required for virus detection, antiviral signaling, inflammation, and clearance of viral infections.26
Although the understanding of MCV is incomplete, several MC proteins have been identified as pivotal host immunomodulators. MC005 protein inhibits NF-κB by binding
