Targeting microbial replication
Direct inhibition of microbial replication is executed by molecules that interfere with specific steps in the replication cycle of a given microorganism. There are at least six mechanisms of action in this category: restriction factors that directly block a specific replication step; restriction factors that deplete molecules essential for replication; RNA interference (RNAi); antimicrobial peptides; soluble lectins; and metabolite-mediated inhibition of microbial replication (Table 1).
execute 실행하다
interfere 간섭하다
restriction 제한
deplete 대폭 감소시키다
interference 간섭
Restrictions factors. - (추후 VHSV, IRIDO를 다룰 때 진행)
Restriction factors are antiviral proteins that target viral replication. Extensive studies, particularly of HIV-1 and herpesviruses, have led to the identification of numerous restriction factors that together target nearly all steps in the viral replication cycle (Fig. 4a).
identification 인지, 발견
For example, APOBEC3 proteins belong to the family of cytidine deaminases, which catalyse the deamination of cytidine to uridine in single-stranded DNA, thus introducing potentially deleterious mutations into the HIV-1 genome. Likewise, tetherin is a membrane-bound protein that prevents the release of progeny HIV-1 particles from the cell surface.
cytidine deaminases 시티딘데아미나아제
cytidine 핵 분해에 의해 얻어지는 뉴클레오시드의 하나인 시토신당
catalyse 촉매작용을 하다
deamination 아미노기 이탈(반응)
deleterious 유해한
mutation 돌연변이
These two mechanisms provide examples of direct blockade of specific steps in the replication cycle. By contrast, SAM domain and HD domain-containing protein 1 (SAMHD1) blocks HIV-1 replication indirectly, by converting deoxynucleoside triphosphates into inorganic phosphate and 2′-deoxynucleoside, thus depleting essential building blocks for HIV-1 reverse transcription. The aforementioned restriction factors work in the plasma membrane or in the cytoplasm. However, many DNA viruses, including herpesviruses, replicate in the nucleus, where they are also targeted by numerous restriction factors. These include nuclear domain 10 bodies (ND10 bodies) and IFNγ-inducible protein 16 (IFI16), which operate by different mechanisms to epigenetically silence viral genomes. The herpesvirus DNA rapidly associates with ND10 bodies, which restrict viral gene expression by promoting processes that lead to the formation of nucleosome-like structures. IFI16 restricts viral replication in the nucleus mainly by interfering directly with transcription35. New evidence suggests that this involves the ability of IFI16 to form DNA filaments, which reduces recruitment of RNA polymerase II (ref. 43), but also leads to recruitment of ND10 bodies, thus indicating that these two restriction systems might interact. The restriction factors discussed here are all constitutively expressed, although the expression of many of them is further increased by interferons. Tonic type I interferon signalling or constitutive activity of interferon regulatory factor 1 (IRF1) drives the basal expression of many constitutive restriction factors.
RNA interference.
RNAi is another constitutive immune mechanism that directly controls viral replication. RNAi involves the processing of double-stranded RNA molecules by members of the Dicer nuclease family to 20–25-bp fragments, thus leading to the formation of the RNA-induced silencing complex (RISC), which blocks gene expression or translation through binding to target mRNAs. The ability of RNAi to directly block viral replication was first shown in plants49 and was later also shown in insects and worms. For example, Caenorhabditis elegans and Drosophila melanogaster infected with Flock House virus activate antiviral defence mechanisms that depend on Dicer. This constitutive immune mechanism might have a more important role in lower organisms, but as some mammalian viruses do target the RNAi system, there may be a subdominant role for this primordial antiviral system in host defence in more evolved organisms. For example, Ebola virus VP35 and VP30 proteins interact with Dicer cofactors, and the hepatitis C virus core protein directly associates with Dicer.
Antimicrobial peptides.
Antimicrobial peptides, including defensins and cathelicidins, contribute to the first line of defence against bacteria in the skin and at mucosal surfaces. They work by binding directly to bacterial membranes, thus perturbing membrane integrity and inhibiting microbial growth. These peptides are rich in both cationic and hydrophobic amino acids, and generally form amphiphilic helical structures, although this may not be the case for all antimicrobial peptides. This enables the peptides to interact with negatively charged bacterial surfaces through electrostatic interactions, thus triggering disruption of the bacterial membranes by pore-forming or non-pore-forming mechanisms.
perturbe 동요하게 하다
integrity 완전한 상태
cationic 양이온
hydrophobic amino acid 소수성 아미노산
amphiphilic 양쪽 친매성
helical 나선의
trigger 촉발시키다
disruption 지장, 방해
Many antimicrobial peptides, such as β-defensin 1, are constitutively expressed on epithelial surfaces, thus providing immediate antimicrobial action on infection. This is illustrated by the increased susceptibility to a broad range of bacterial infections in mice lacking cathelicidin antimicrobial peptide (CAMP).
constitutively 본질적으로
illustrate 분명히 보여주다
susceptibility 민감성
Beyond their role in antibacterial defence, there is also evidence that antimicrobial peptides can disrupt viral particles, thus exerting antiviral activity. Similarly to the restriction factors, many antimicrobial peptides are expressed in both constitutive and inducible manners. This illustrates the general principle that different branches of the immune system can use overlapping effector functions (Box 2).
Box2 | Overlap between constitutive and inducible immune responses In most respects, constitutive and inducible immune responses operate through different principles; however, in certain cases, their downstream effector activities may overlap. This is to be expected given that all of these responses use mechanisms from the same ‘evolutionary toolbox’ to achieve optimal protection of the host. For example, autophagy can be activated during infection and upon sterile danger. Similarly, phagocytosis can be activated by both Toll-like receptor (TLR)-dependent and TLRindependent mechanisms. Moreover, many restriction factors are expressed at basal levels to exert immediate antiviral activity, but are also induced transcriptionally in response to stimulation with type I interferon. Nevertheless, despite these minor areas of overlap between constitutive immune mechanisms and the pattern recognition receptor (PRR)-induced immune responses, the differences are more pronounced. The key difference between constitutive immune mechanisms and PRR induced immunity is that the former mechanisms are all activated through pre-existing molecules to directly eliminate danger, whereas the latter system functions mainly through inducible transcription-dependent proinflammatory programmes. In addition, inducible innate responses can amplify adaptive responses, whereas constitutive innate responses do not amplify inducible innate responses.
Soluble lectins.
Many microorganisms have extensive and more complex glycan patterns than mammalian cells, and these sugars can therefore be used as a means to distinguish self from non-self. There are four classes of soluble lectins carrying out this function, namely collectins, ficolins, galectins and pentraxins. On recognition of non-self glycans, soluble lectins can exert host defence activities indirectly through complement activation and opsonization, as discussed later, or directly through aggregation and neutralization. For example, the collectin surfactant protein D (SP-D) has been reported to bind directly to highly glycosylated viruses such as HIV-1 and influenza A virus and neutralize their infectivity68,69. Similarly, pentraxin 3 directly binds influenza A virus particles and neutralizes virus infectivity. Importantly, SP-D-deficient mice have impaired clearance of influenza A virus and increased production of proinflammatory cytokines in response to viral challenge. In addition to viruses, SP-D also binds and agglutinates Streptococcus pneumoniae, thus suggesting that soluble lectins might also have a role in the immediate inactivation of bacteria.
Metabolite-mediated inhibition.
A final example of constitutive immune mechanisms that directly interfere with microbial growth is provided by metabolites that block pathogen replication, and perhaps the best example of which is lactate. Many viral infections are characterized by a shift of host cellular metabolism to aerobic glycolysis, which leads to the production of lactate. Viral infections also induce fatty acid synthesis and intermediate molecules in these pathways. These include palmitic acid and oleic acid, which have been shown to have antiviral activity. The mechanisms by which lactate and other metabolites block viral replication remain to be determined, but the antiviral activity of lactate illustrates a general principle that select molecules accumulating during alterations of cellular homeostasis can interfere with microbial replication. A second form of metabolite-dependent constitutive host defence is mediated through nutritional depletion and starvation of pathogens. For example, natural resistance-associated macrophage protein 1 (NRAMP1; also known as SLC11A1) is a metal ion transporter that transports divalent cations from vacuoles into the cytoplasm, hence depleting factors from vacuoles that are essential for the growth of intracellular pathogens. The gene encoding NRAMP1 was shown to contribute to defence against, for example, Mycobacterium tuberculosis, Salmonella enterica subsp. enterica serovar Typhimurium and Leishmania donovani, which was later shown to be mediated by the reduction of metal ion concentrations inside microorganism-containing vacuoles. A second example of nutritional depletion is provided by lactoferrin, which is present in various secretory fluids. Lactoferrin is a highly cationic molecule that shows antimicrobial activity, in part, by binding and sequestering iron from pathogenic microorganisms. Lactoferrin contributes to host defence in a non-redundant manner, as lactoferrin-deficient mice have increased susceptibility to Streptococcus mutans-induced dental caries, for example.