Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment.

Although the antimicrobial activity of lactoferrin has been well described, its mechanism of action has been poorly characterized. Recent work has indicated that in addition to binding iron, human lactoferrin damages the outer membrane of gram-negative bacteria. In this study, we determined whether bovine lactoferrin and a pepsin-derived bovine lactoferrin peptide (lactoferricin) fragment have similar activities. We found that both 20 microM bovine lactoferrin and 20 microM lactoferricin release intrinsically labeled [3H]lipopolysaccharide ([3H]LPS) from three bacterial strains, Escherichia coli CL99 1-2, Salmonella typhimurium SL696, and Salmonella montevideo SL5222. Under most conditions, more LPS is released by the peptide fragment than by whole bovine lactoferrin. In the presence of either lactoferrin or lactoferricin there is increased killing of E. coli CL99 1-2 by lysozyme. Like human lactoferrin, bovine lactoferrin and lactoferricin have the ability to bind to free intrinsically labeled [3H]LPS molecules. In addition to these effects, whereas bovine lactoferrin was at most bacteriostatic, lactoferricin demonstrated consistent bactericidal activity against gram-negative bacteria. This bactericidal effect is modulated by the cations Ca2+, Mg2+, and Fe3+ but is independent of the osmolarity of the medium. Transmission electron microscopy of bacterial cells exposed to lactoferricin show the immediate development of electron-dense "membrane blisters." These experiments offer evidence that bovine lactoferrin and lactoferricin damage the outer membrane of gram-negative bacteria. Moreover, the peptide fragment lactoferricin has direct bactericidal activity. As lactoferrin is exposed to proteolytic factors in vivo which could cleave the lactoferricin fragment, the effects of this peptide are of both mechanistic and physiologic relevance.     

PspA protects Streptococcus pneumoniae from killing by apolactoferrin, and antibody to PspA enhances killing of pneumococci by apolactoferrin [corrected

Lactoferrin is an important component of innate immunity through its sequestration of iron, bactericidal activity, and immune modulatory activity. Apolactoferrin (ALF) is the iron-depleted form of lactoferrin and is bactericidal against pneumococci and several other species of bacteria. We observed that lactoferricin (LFN), an 11-amino-acid peptide from the N terminus of lactoferrin, is bactericidal for Streptococcus pneumoniae. Strains of S. pneumoniae varied in their susceptibility to ALF. Lactoferrin is bound to the pneumococcal surface by pneumococcal surface protein A (PspA). Using mutant PspA(-) pneumococci of four different strains, we observed that PspA offers significant protection against killing by ALF. Knockout mutations in genes for two other choline-binding proteins (PspC and PcpA) did not affect killing by ALF. PspA did not have to be attached to the bacterial surface to inhibit killing, because the soluble recombinant N-terminal half of PspA could prevent killing by both ALF and LFN. An 11-amino-acid fragment of PspA was also able to reduce the killing by LFN. Antibody to PspA enhanced killing by lactoferrin. These findings suggested that the binding of ALF to PspA probably blocks the active site(s) of ALF that is responsible for killing.     

Effect of lactoferricin B,a pepsin-generated peptide of bovine lactoferrin,on Escherichia coli HB101 (pRI203) entry into HeLa cells

Bovine lactoferrin and a pepsin-generated peptide of bovine lactoferrin, known as lactoferricin B, were tested for an ability to influence the cell-invasive properties of an Escherichia coli HB101 strain carrying the plasmid pRI203, which encodes the Yersinia pseudotuberculosis inv gene. At non-cytotoxic and non-bactericidal concentration (0.5 mg/ml) lactoferricin B lowered by about tenfold the cell invasion capability of E. coli HB101 (pRI203), whereas no effect was observed when bovine lactoferrin was added during the infection of HeLa cell monolayers. The step of the invasion process affected by lactoferricin B was the internalization since the adhesion of bacteria to HeLa cells was unaltered in the presence of the peptide. Latex beads coated with lactoferricin B bound to HeLa cell monolayers and induced the agglutination of bacterial cells, indicating that this highly cationic peptide interacts directly with both eukaryotic and bacterial surfaces. Moreover, we demonstrated that the anti-invasive effect induced by lactoferricin B was reversed when the medium was supplemented with Ca²⁺, Mg²⁺ and Fe²⁺ ions which diminished its affinity binding. Our findings suggest that lactoferricin B effectiveness towards E. coli HB101 (pRI203) invasion is correlated to its binding capability on the eukaryotic and bacterial cell surfaces.     

Characterization of antiviral activity of lactoferrin against hepatitis C virus infection in human cultured cells

We recently found that bovine lactoferrin (bLF), a milk glycoprotein belonging to the iron transporter family, prevented hepatitis C virus (HCV) infection in human hepatocyte PH5CH8 cells, that are susceptible to HCV infection, and demonstrated that the anti-HCV activity of bLF was due to the interaction of bLF and HCV. In this study we further characterized the anti-HCV activity of bLF and the mechanism by which bLF prevents HCV infection. We found that bLF inhibited viral entry to the cells by interacting directly with HCV immediately after mixing of bLF and HCV inoculum. The anti-HCV activity of bLF was lost by heating at 65 degrees C, and other milk proteins (mucin, beta-lactoglobulin and casein) did not prevent HCV infection, indicating that bLF prevented HCV infection in a rather specific manner. Furthermore, we found that bovine lactoferricin, a basic N-terminal loop of bLF that is an important region for antibacterial activity, did not exhibit any anti-HCV activity, suggesting that some other region is involved in anti-HCV activity. We confirmed that prevention of HCV infection by bLF was a general phenomenon, because bLF inhibited HCV infection with all five inocula examined, and bLF inhibited HCV infection in human MT-2C T-cells, that were susceptible to HCV infection. In addition, infection with hepatitis G virus, which is distantly related to HCV, was prevented also by bLF. In conclusion, lactoferrin is a natural glycoprotein which effectively protects against HCV infection in hepatocytes and lymphocytes by neutralizing the virus.     

One of two human lactoferrin variants exhibits increased antibacterial and transcriptional activation activities and is associated with localized juvenile periodontitis

The iron-binding protein lactoferrin is a ubiquitous and abundant constituent of human exocrine secretions. Lactoferrin inhibits bacterial growth by sequestering essential iron and also exhibits non-iron-dependent antibacterial, antifungal, antiviral, antitumor, anti-inflammatory, and immunoregulatory activities. All of these non-iron-dependent activities are mediated by the highly charged N terminus of lactoferrin. In this study we characterized a Lys/Arg polymorphism at position 29 in the N-terminal region of human lactoferrin that results from a single nucleotide polymorphism in exon 1 of the human lactoferrin gene. We expressed cDNAs encoding both lactoferrin variants in insect cells and purified the two proteins by ion exchange chromatography. The two lactoferrin variants exhibited nearly identical iron-binding and iron-releasing activities and equivalent bactericidal activities against a strain of the gram-negative bacterium Actinobacillus actinomycetemcomitans. When tested against the gram-positive species Streptococcus mutans and Streptococcus mitis, however, lactoferrin containing Lys at position 29 exhibited significantly greater bactericidal activity than did lactoferrin containing Arg. In addition, the Lys-containing lactoferrin stimulated bovine tracheal epithelial cells to synthesize much higher levels of tracheal antimicrobial peptide mRNA than did the Arg-containing variant. A genotyping assay that distinguished between the two alleles based on a polymorphic EarI restriction site showed that the Lys and Arg alleles had frequencies of 24% and 76%, respectively, among 17 healthy human subjects, and 72% and 28%, respectively, among nine patients with localized juvenile periodontitis. Our findings suggest that these two lactoferrin variants are functionally different and that these differences may contribute to the pathogenesis of localized juvenile periodontitis.     

Antiviral activity of human lactoferrin: inhibition of alphavirus interaction with heparan sulfate

Human lactoferrin is a component of the non-specific immune system with distinct antiviral properties. We used alphaviruses, adapted to interaction with heparan sulfate (HS), as a tool to investigate the mechanism of lactoferrin's antiviral activity. Lactoferrin inhibited infection of BHK-21 cells by HS-adapted, but not by non-adapted, Sindbis virus (SIN) or Semliki Forest virus (SFV). Lactoferrin also inhibited binding of radiolabeled HS-adapted viruses to BHK-21 cells or liposomes containing lipid-conjugated heparin as a receptor analog. On the other hand, low-pH-induced fusion of the viruses with liposomes, which occurs independently of virus-receptor interaction, was unaffected. Studies involving preincubation of virus or cells with lactoferrin suggested that the protein does not bind to the virus, but rather blocks HS-moieties on the cell surface. Charge-modified human serum albumin, with a net positive charge, had a similar antiviral effect against HS-adapted SIN and SFV, suggesting that the antiviral activity of lactoferrin is related to its positive charge. It is concluded that human lactoferrin inhibits viral infection by interfering with virus-receptor interaction rather than by affecting subsequent steps in the viral cell entry or replication processes.     

Recombinant adenovirus vectors expressing interleukin-5 and -6 specifically enhance mucosal immunoglobulin A responses in the lung

In this study, we have examined the in vivo effects of interleukin-5 (IL-5) and IL-6 over-expression on systemic and mucosal immune responses using recombinant human type 5 adenoviruses capable of expressing these cytokines upon infection. A recombinant adenovirus containing the murine IL-5 gene within the E3 region was constructed and found to express high levels of IL-5 protein both in vitro and in vivo. Intranasal inoculation of mice with this vector or a vector expressing murine IL-6 increased adenovirus-specific immunoglobulin A (IgA) titres in lung lavage fluid threefold compared with those elicited by control virus. The simultaneous expression of both cytokines by co-inoculation altered the kinetics of the mucosal anti-adenovirus IgA response and resulted in a more than additive increase in antibody titres. The co-expression effect on IgA synthesis was not due to an increase in numbers of antigen-specific resident lung tissue lymphocytes. When mucosal IgG responses were examined, IL-6 expression had the largest impact on anti-adenovirus levels, whereas co-expression produced an intermediate response. Systemic immune responses were also affected by IL-6 expression as a twofold increase in serum IgG anti-adenovirus titres was observed after a secondary challenge with wild-type adenovirus. These results demonstrate a relevant role for IL-5 and IL-6 in the development of mucosal immune responses in vivo and suggest that the incorporation of either IL-5 and/or IL-6 into recombinant adenovirus vectors may be a useful tool in the development of mucosal vaccines.     

Bovine lactoferrin inhibits Japanese encephalitis virus by binding to heparan sulfate and receptor for low density lipoprotein

Lactoferrin is a natural anti-microbial protein which affects Japanese encephalitis virus (JEV) activity. Binding of lactoferrin to cell surface expressed heparan sulfate (HS), one possible receptor for JEV, has been postulated to be the possible mechanism of anti-JEV antiviral activity. In this study, we evaluate the effects of bovine lactoferrin (bLF) against JEV infection in vitro, using both wild-type (WT) and laboratory-adapted strains. bLF inhibited the infectivity of all the JEV strains tested. In particular the infectivity of the HS-adapted JEV strains was strongly reduced, whereas the non HS-adapted JEV strains were inhibited to lesser extent. Using both HS-adapted CJN-S1 and non HS-adapted CJN-L1 viruses, the results showed that bLF inhibited the early events essential to initiate JEV infection, which includes blocking virus attachment to cellular membranes and reducing viral penetration. This anti-JEV activity was the highest using HS-adapted CJN-S1 strain on HS-expressed CHO-K1 cells. Also, binding of bLF to heparin-sepharose blocked JEV binding; and soluble HS attenuated the anti-JEV activity of bLF. The results support the premise that the interaction of bLF with cell surface expressed glycosaminoglycans, in particular the highly sulfated HS, plays an essential role in the antiviral activity of bLF. However, bLF was functional in inhibiting CJN-S1 entry into HS-deficient CHO-pgsA745 cells, and bLF-treated CHO-K1 and -pgsA745 cells also prevented non HS-adapted CJN-L1 virus entry, indicating that a non-HS pathway may be involved in bLF inhibition of JEV entry. The low-density lipoprotein receptor (LDLR), possibly involved in the entry of several RNA viruses, also binds to bLF. We found that both rLDLR and anti-LDLR antibodies reduced the effectiveness of bLF inhibition of JEV infection. This finding provided evidence to suggest that cell surface-expressed LDLR may play a role in JEV infection, especially for non HS-adapted strains.     

Serine protease PrtA from Streptococcus pneumoniae plays a role in the killing of S. pneumoniae by apolactoferrin

It is known that apolactoferrin, the iron-free form of human lactoferrin, can kill many species of bacteria, including Streptococcus pneumoniae. Lactoferricin, an N-terminal peptide of apolactoferrin, and fragments of it are even more bactericidal than apolactoferrin. In this study we found that apolactoferrin must be cleaved by a serine protease in order for it to kill pneumococci. The serine protease inhibitors were able to block killing by apolactoferrin but did not block killing by a lactoferrin-derived peptide. Thus, the killing of pneumococci by apolactoferrin appears to require a protease to release a lactoferricin-like peptide(s). Incubation of apolactoferrin with growing pneumococci resulted in a 12-kDa reduction in its molecular mass, of which about 7 to 8 kDa of the reduction was protease dependent. Capsular type 2 and 19F strains with mutations in the gene encoding the major cell wall-associated serine protease, prtA, lost much of their ability to degrade apolactoferrin and were relatively resistant to killing by apolactoferrin (P < 0.001). Recombinant PrtA was also able to cleave apolactoferrin, reducing its mass by about 8 kDa, and greatly enhance the killing activity of the solution containing the apolactoferrin and its cleavage products. Mass spectroscopy revealed that PrtA makes a major cut between amino acids 78 and 79 of human lactoferrin, removing the N-terminal end of the molecule (about 8.6 kDa). The simplest interpretation of these data is that the mechanism by which apolactoferrin kills Streptococcus pneumoniae requires the release of a lactoferricin-like peptide(s) and that it is this peptide(s), and not the intact apolactoferrin, which kills pneumococci.     

Killing of Candida albicans by lactoferricin B,a potent antimicrobial peptide derived from the N-terminal region of bovine lactoferrin

Candida albicans was found to be highly susceptible to inhibition and inactivation by lactoferricin B, a peptide produced by enzymatic cleavage of bovine lactoferrin. Effective concentrations of the peptide varied within the range of 18 to 150 g/ml depending on the strain and the culture medium used. Its effect was lethal, causing a rapid loss of colony-forming capability. ¹⁴C-labeled lactoferricin B bound to C. albicans and the rate of binding appeared to be consistent with the rate of killing induced by the peptide. The extent of binding was diminished in the presence of Mg²⁺ or Ca²⁺ ions which acted to reduce its anticandidal effectiveness. Binding occurred optimally at pH 6.0 and killing was maximal near the same pH. Such evidence suggests the lethal effect of lactoferricin B results from its direct interaction with the cell surface. Cells exposed to lactoferricin B exhibited profound ultrastructural damage which appeared to reflect its induction of an autolytic response. These findings suggest that active peptides of lactoferrin could potentially contribute to the host defense against C. albicans.     

Lactoferrin-mediated protection of the host from murine cytomegalovirus infection by a T-cell-dependent augmentation of natural killer cell activity

Summary The administration of bovine lactoferrin (LF) with 1 mg/g body weight before the murine cytomegalovirus (MCMV) infection completely protected the BALB/c mice from death due to the infection. In these LF-treated mice, a significant increase in the activity was found in the NK cells but not in the cytolytic T lymphocytes which recognized an MCMV-derived peptide. Moreover, the elimination of the NK cell activity by an injection with anti-asialo GM1 antibody abrogated such augmented resistance, thus supporting the hypothesis that the LF-mediated antiviral effect in vivo is performed through the augmentation of NK cell activity. No such LF-mediated antiviral effect in vivo with the increased NK cell activity was found in athymic nude mice, whereas it was restored completely by the transfer of splenic T cells from LF-treated donors. These findings therefore suggest that T lymphocytes induce both the augmentation of NK cell activity and the resultant antiviral effect in the LF-treated hosts.     

Camel lactoferrin markedly inhibits hepatitis C virus genotype 4 infection of human peripheral blood leukocytes

Hepatitis C virus (HCV) is a serious worldwide health risk and, to date, no effective treatments to prevent progression to chronic infection have been discovered. To combat the disease, Egyptian patients often use traditional medicines, for instance, camel milk, which contains lactoferrin. Currently, lactoferrin is one of the primary biopharmaceutical drug candidates against HCV infection. Camel lactoferrin (cLf) purification and biochemical and immunological characterization have shown its similarity to human and bovine lactoferrin, and crossreacts with the anti-human lactoferrin antibody. Incubation of human leukocytes with cLf then infected with HCV did not prevent the HCV entry into the cells, while the direct interaction between the HCV and cLf leads to a complete virus entry inhibition after seven days incubation. Our results suggest that the cLf may be one of the camel milk components having antiviral activity. In conclusion, we have demonstrated the potential for cLf to inhibit HCV entry into human leukocytes with more efficiency than human or bovine lactoferrin.     

Inhibition of herpes simplex virus infection by lactoferrin is dependent on interference with the virus binding to glycosaminoglycans

Previous reports have indicated that lactoferrin inhibits herpes simplex virus (HSV) infection during the very early phases of the viral replicative cycle. In the present work we investigated the mechanism of the antiviral activity of lactoferrin in mutant glycosaminoglycan (GAG)-deficient cells. Bovine lactoferrin (BLf) was a strong inhibitor of HSV-1 infection in cells expressing either heparan sulfate (HS) or chondroitin sulfate (CS) or both, but was ineffective or less efficient in GAG-deficient cells or in cells treated with GAG-degrading enzymes. In contrast to wild-type HSV-1, virus mutants devoid of glycoprotein C (gC) were significantly less inhibited by lactoferrin in GAG-expressing cells, indicating that lactoferrin interfered with the binding of viral gC to cell surface HS and/or CS. Finally, we demonstrated that lactoferrin bound directly to both HS and CS isolated from surfaces of the studied cells, as well as to commercial preparations of GAG chains. The results support the hypothesis that the inhibition of HSV-1 infectivity by lactoferrin is dependent on its interaction with cell surface GAG chains of HS and CS.     

Anti-HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface

Lactoferrin (LF) is a multifunctional glycoprotein, which plays an important role in immune regulation and defense mechanisms against bacteria, fungi, and viruses. Lactoferricin (Lfcin) is a potent antimicrobial peptide generated from the N-terminal part of LF by pepsin cleavage. In this study, we investigated the mechanisms of the anti-herpes simplex virus (anti-HSV) activity of LF and Lfcin. The results demonstrated that LF and Lfcin inhibited the entry of HSV into Vero cells. LF had no effect against HSV after the virus had entered the cells, while Lfcin exerted antiviral activity also after the initial binding of the virus to the host cell. The distribution of LF and Lfcin in the cells was investigated by immunogold-labeling and transmission electron microscope (TEM). LF was found mainly at the cell surface in cells expressing heparan sulphate. Lfcin was randomly distributed intracellularly. LF must be present at the cell surface to exert antiviral activity, while Lfcin exert its antiviral activity also when found mainly intracellularly. Both LF and Lfcin were dependent on the presence of heparan sulphate at the cell surface to exert their antiviral activity.     

Poly I:C-induced antiviral and cytotoxic activities are mediated by different mechanisms

Macrophages play an important role in host defenses against tumors and virus infections by killing tumor or virus infected cells (extrinsic cytotoxicity) and by limiting virus replication within themselves (intrinsic antiviral activity). Since common macrophage products may be involved in both extrinsic cytotoxicity and intrinsic antiviral activity, we decided to investigate the mechanisms by which Poly I:C-activated macrophages resist infection with HSV-1 and inhibit the growth of tumor cells. The ability of macrophages to resist infection with HSV-1 or to inhibit growth of tumor cells was assessed following treatment with Poly I:C in the presence of antibodies to various cytokines or in the presence of inhibitors/scavengers of toxic macrophage products. Only antibodies to IFN-β were able to abrogate the protective effects of Poly I:C in macrophages infected with HSV-1, suggesting that the antiviral activity induced by this immunomodulator was mediated by the production of IFN-β, which acted in an autocrine manner. In contrast, anti-TNF-α, anti-IFN-α/β, anti-IFN-β antibodies and inhibitors of nitric oxide and C1q production were all able to partially abrogate Poly I:C-induced cytostatic activity, suggesting that multiple mechanisms are involved in macrophage cytostasis. Our results indicate the Poly I:C-induced intrinsic antiviral and extrinsic cytotoxic activities are mediated by different mechanisms.     

Characterization of the anti‐HBV activity of HLP1–23, a human lactoferrin‐derived peptide

Lactoferrin (Lf) was shown to exhibit its antiviral activity at an early phase of viral infection and a mechanism whereby the protein interacts with host cell surface molecules has been suggested. In this study, human Lf (HLf) and seven HLf‐derived synthetic peptides (HLP) corresponding to the N‐terminal domain of the native protein (1–47 amino acids sequence) were assayed for their capacity to prevent hepatitis B virus (HBV) infection and replication using the HepaRG and HepG2.2.2.15 cell lines. Of the series tested, four peptides showed 40–75% inhibition of HBV infection in HepaRG cells, HLP_1–23, containing the GRRRR cationic cluster, being the most potent. Interestingly, this cluster is one of the two glycosaminoglycan binding sites of the native HLf involved in its antiviral activity; however, the mechanism of the HLP_1–23 action was different from that of the full‐length protein, the peptide inhibiting HBV infection when pre‐incubated with the virus, while no effect was observed on the target cells. It is suggested that the cationic cluster is sufficient for the peptide to interact stably with negatively charged residues on the virion envelope, while the absence of the second glycosaminoglycan binding site prevents its efficient attachment to the cells. In conclusion, this peptide may constitute a non‐toxic approach for potential clinical applications in inhibiting HBV entry by neutralizing the viral particles. J. Med. Virol. 85:780–788, 2013. © 2013 Wiley Periodicals, Inc.     

肉桂醛抗腺病毒作用研究

目的: 研究肉桂醛抗腺病毒(ADV)作用。方法: 采用噻唑蓝(MTT)比色法和病毒增殖抑制实验观测肉桂醛抗ADV作用;免疫荧光法检测肉桂醛对ADV六邻体(hexon)蛋白表达的影响。结果: (1)MTT和病毒增殖抑制实验结果表明肉桂醛在3种作用方式(除细胞保护作用方式)下能够增强宿主细胞存活率,降低病毒滴度,且细胞存活率与药物浓度呈正相关,肉桂醛对宿主细胞无保护作用,不能阻断病毒进入细胞。(2)肉桂醛(除细胞保护作用方式)组与病毒组比较hexon蛋白的表达明显降低(P<0.05)。结论: 肉桂醛有抗ADV作用,但却对宿主细胞无保护作用,肉桂醛抗ADV作用可能与调节hexon蛋白的表达有关。     

The gamma interferon (IFN-gamma) mimetic peptide IFN-gamma (95-133) prevents encephalomyocarditis virus infection both in tissue culture and in mice

We have demonstrated previously that the C-terminal gamma interferon (IFN-gamma) mimetic peptide consisting of residues 95 to 133 [IFN-gamma(95-133)], which contains the crucial IFN-gamma nuclear localization sequence (NLS), has antiviral activity in tissue culture. Here we evaluate the efficacy of this peptide and its derivatives first in vitro and then in an animal model of lethal viral infection with the encephalomyocarditis (EMC) virus. Deletion of the NLS region from the IFN-gamma mimetic peptide IFN-gamma(95-133) resulted in loss of antiviral activity. However, the NLS region does not have antiviral activity in itself. Replacing the NLS region of IFN-gamma(95-133) with the NLS region of the simian virus 40 large T antigen retains the antiviral activity in tissue culture. IFN-gamma(95-133) prevented EMC virus-induced lethality in mice in a dose-dependent manner compared to controls. Mice treated with IFN-gamma(95-133) had no or low EMC virus titers in their internal organs, whereas control mice had consistently high viral titers, especially in the heart tissues. Injection of B8R protein, which is encoded by poxviruses as a defense mechanism to neutralize host IFN-gamma, did not inhibit IFN-gamma(95-133) protection against a lethal dose of EMC virus, whereas mice treated with rat IFN-gamma were not protected. The data presented here show that the IFN-gamma mimetic peptide IFN-gamma(95-133) prevents EMC virus infection in vivo and in vitro and may have potential against other lethal viruses, such as the smallpox virus, which encodes the B8R protein.     

Cloning, characterization, and biological function analysis of the SidT2 gene from Siniperca chuatsi

The systemic RNA interference defective protein (SID)-1 plays an important role in dsRNA uptake in cells. We identified the ScSidT2 gene from the mandarin fish (Siniperca chuatsi), which is the first-studied SID-1 homolog in fish. ScSidT2 mRNA is 3380 bp long and contains a 2568-bp open reading frame that encodes an 855-amino-acid protein with an N-terminal signal peptide and ten putative transmembrane domains. Tissue distribution profile in healthy fish and expression profiles of ScSidT2 in infectious spleen and kidney necrosis virus (ISKNV)-infected fish were analyzed. Overexpression of the ScSidT2 protein in fathead minnow (FHM) epithelial cells could remarkably increase the uptake of exogenous dsRNA. In tiger frog virus (TFV)-infected FHM cells, overexpression of ScSidT2 could suppress virus production, and this mechanism could be significantly enhanced by adding virus-specific dsRNA. In mandarin fish fry cells, ISKNV infection and reproduction could be promoted when the ScSidT2 protein was neutralized with specific antisera. These results suggest that ScSidT2 could be associated with the host's antiviral defense mechanism.