The Role of Innate Immunity in Regulating Rotavirus Replication, Pathogenesis, and Host Range Restriction and the Implications for Live Rotaviral Vaccine Development

ABSTRACT Avian influenza virus (AIV) can cross species barriers to infect humans and other mammals. However, these species-cross transmissions are most often dead-end infections due to host restriction. Current research about host restriction focuses mainly on the barriers of cell membrane, nuclear envelope, and host proteins; whether microRNAs (miRNAs) play a role in host restriction is largely unknown. In this study, we used porcine alveolar macrophage (PAM) cells as a model to elucidate the role of miRNAs in host range restriction. During AIV infection, 40 dysregulation expressed miRNAs were selected in PAM cells. Among them, two Sus scrofa (ssc; swine) miRNAs, ssc-miR-221-3p and ssc-miR-222, could inhibit the infection and replication of AIV in PAM cells by directly targeting viral genome and inducing cell apoptosis via inhibiting the expression of anti-apoptotic protein HMBOX1. Avian but not swine influenza virus caused upregulated expressions of ssc-miR-221-3p and ssc-miR-222 in PAM cells. We further found that NF-κB P65 was more effectively phosphorylated upon AIV infection and that P65 functioned as a transcription activator to regulate the AIV-induced expression of miR-221-3p/222. Importantly, we found that ssc-miR-221-3p and ssc-miR-222 could also be specifically upregulated upon AIV infection in newborn pig tracheal epithelial (NPTr) cells and also exerted anti-AIV function. In summary, our study indicated that miRNAs act as a host barrier during cross-species infection of influenza A virus. IMPORTANCE The host range of an influenza A virus is determined by species-specific interactions between virus and host cell factors. Host miRNAs can regulate influenza A virus replication; however, the role of miRNAs in host species specificity is unclear. Here, we show that the induced expression of ssc-miR-221-3p and ssc-miR-222 in swine cells is modulated by NF-κB P65 phosphorylation in response to AIV infection but not swine influenza virus infection. ssc-miR-221-3p and ssc-miR-222 exerted antiviral function via targeting viral RNAs and causing apoptosis by inhibiting the expression of HMBOX1 in host cells. These findings uncover miRNAs as a host range restriction factor that limits cross-species infection of influenza A virus.

Download Full-text

A cysteine/methionine auxotroph of the opportunistic fungus Aspergillus flavus is associated with host-range restriction: a model for emerging diseases

Microbiology ◽

10.1099/mic.0.28452-0 ◽

2006 ◽

Vol 152 (1) ◽

pp. 223-232 ◽

Cited By ~ 21

Author(s):

Lisa R. Scully ◽

Michael J. Bidochka

Keyword(s):

Host Range ◽

Aspergillus Flavus ◽

Emerging Diseases ◽

Host Specialization ◽

Insect Host ◽

Range Restriction ◽

Host Restriction ◽

Agar Media ◽

Host Range Restriction

The evolution of host specialization in pathogens is a topic of considerable interest, particularly since it can represent a decisive step in the emergence of infectious diseases. Aspergillus flavus is an opportunistic fungus capable of infecting a wide variety of hosts, including plants, insects and mammals, although with low virulence. Here the derivation of an A. flavus strain that exhibits severe host restriction is reported. This strain exhibited a severe diminution or a complete lack of conidial production on a variety of standard agar media and on various plant species. However, it retained its ability to infect insects from various orders and to re-emerge from and adequately conidiate on the insect cadavers as a culmination of the pathogenic life cycle. This strain, demonstrating insect-dependent conidiation, was discovered to be a cysteine/methionine auxotroph due to an inability to reduce sulfate to sulfite. However, other A. flavus auxotrophs tested for plant and insect host range failed to show insect-dependent conidiation. An association between this specific auxotroph and a decreased host range is shown, emphasizing the role of nutrition in the host–pathogen relationship with respect to host restriction and evolution towards obligate pathogenesis.

Download Full-text

A host range restriction in infectious pancreatic necrosis virus maps to the large RNA segment and involves virus attachment to the cell surface

Virology ◽

10.1016/0042-6822(82)90260-4 ◽

1982 ◽

Vol 123 (2) ◽

pp. 264-272 ◽

Cited By ~ 5

Author(s):

E.Anne Arragh ◽

Richard D. Macdonald

Keyword(s):

Cell Surface ◽

Host Range ◽

Pancreatic Necrosis ◽

Infectious Pancreatic Necrosis Virus ◽

Necrosis Virus ◽

Range Restriction ◽

Virus Attachment ◽

Infectious Pancreatic Necrosis ◽

Pancreatic Necrosis Virus ◽

Host Range Restriction

Download Full-text

Analysis of Host Range Restriction Determinants in the Rabbit Model: Comparison of Homologous and Heterologous Rotavirus Infections

Journal of Virology ◽

10.1128/jvi.72.3.2341-2351.1998 ◽

1998 ◽

Vol 72 (3) ◽

pp. 2341-2351 ◽

Cited By ~ 34

Author(s):

Max Ciarlet ◽

Mary K. Estes ◽

Christopher Barone ◽

Robert F. Ramig ◽

Margaret E. Conner

Keyword(s):

Host Range ◽

Model Comparison ◽

Rabbit Model ◽

Productive Infection ◽

Complete Protection ◽

Range Restriction ◽

Rotavirus Infection ◽

Replication Efficiency ◽

Host Range Restriction ◽

Rotavirus Infections

ABSTRACT The main limitation of both the rabbit and mouse models of rotavirus infection is that human rotavirus (HRV) strains do not replicate efficiently in either animal. The identification of individual genes necessary for conferring replication competence in a heterologous host is important to an understanding of the host range restriction of rotavirus infections. We recently reported the identification of the P type of the spike protein VP4 of four lapine rotavirus strains as being P[14]. To determine whether VP4 is involved in host range restriction in rabbits, we evaluated infection in rotavirus antibody-free rabbits inoculated orally with two P[14] HRVs, PA169 (G6) and HAL1166 (G8), and with several other HRV strains and animal rotavirus strains of different P and G types. We also evaluated whether the parental rhesus rotavirus (RRV) (P5B[3], G3) and the derived RRV-HRV reassortant candidate vaccine strains RRV × D (G1), RRV × DS-1 (G2), and RRV × ST3 (G4) would productively infect rabbits. Based on virus shedding, limited replication was observed with the P[14] HRV strains and with the SA11 Cl3 (P[2], G3) and SA11 4F (P6[1], G3) animal rotavirus strains, compared to the homologous ALA strain (P[14], G3). However, even limited infection provided complete protection from rotavirus infection when rabbits were challenged orally 28 days postinoculation (DPI) with 103 50% infective doses of ALA rabbit rotavirus. Other HRVs did not productively infect rabbits and provided no significant protection from challenge, in spite of occasional seroconversion. Simian RRV replicated as efficiently as lapine ALA rotavirus in rabbits and provided complete protection from ALA challenge. Live attenuated RRV reassortant vaccine strains resulted in no, limited, or productive infection of rabbits, but all rabbits were completely protected from heterotypic ALA challenge. The altered replication efficiency of the reassortants in rabbits suggests a role for VP7 in host range restriction. Also, our results suggest that VP4 may be involved in, but is not exclusively responsible for, host range restriction in the rabbit model. The replication efficiency of rotavirus in rabbits also is not controlled by the product of gene 5 (NSP1) alone, since a reassortant rotavirus with ALA gene 5 and all other genes from SA11 was more severely replication restricted than either parental rotavirus strain.

Download Full-text

Host Range Restriction of Epstein-Barr Virus and Related Lymphocryptoviruses

Journal of Virology ◽

10.1128/jvi.01235-15 ◽

2015 ◽

Vol 89 (17) ◽

pp. 9133-9136 ◽

Cited By ~ 7

Author(s):

Janine Mühe ◽

Fred Wang

Keyword(s):

B Cells ◽

Host Range ◽

Epstein Barr Virus ◽

Nonhuman Primates ◽

Range Restriction ◽

Barr Virus ◽

Epstein Barr ◽

Multiple Species ◽

High Degree ◽

Host Range Restriction

Epstein-Barr-related herpesviruses, or lymphocryptoviruses (LCV), naturally infect humans and nonhuman primates (NHP), but their host range is not well characterized. Using LCV and B cells from multiple species of Hominidae and Cercopithecidae, we show that LCV can immortalize B cells from some nonnative species but that growth transformation is restricted to B cells from their own family of hominoids or Old World NHP, suggesting a high degree of LCV adaptation to their natural primate host.

Download Full-text

Determinants of the Host Range Restriction of Replication of Bovine Parainfluenza Virus Type 3 in Rhesus Monkeys Are Polygenic

Journal of Virology ◽

10.1128/jvi.77.2.1141-1148.2003 ◽

2003 ◽

Vol 77 (2) ◽

pp. 1141-1148 ◽

Cited By ~ 26

Author(s):

Mario H. Skiadopoulos ◽

Alexander C. Schmidt ◽

Jeffrey M. Riggs ◽

Sonja R. Surman ◽

William R. Elkins ◽

...

Keyword(s):

Respiratory Tract ◽

Host Range ◽

Rhesus Monkeys ◽

Single Unit ◽

Parainfluenza Virus ◽

Wild Type ◽

Range Restriction ◽

Type 3 ◽

Bovine Parainfluenza Virus ◽

Host Range Restriction

ABSTRACT The Kansas strain of bovine parainfluenza virus type 3 (BPIV3) is 100- to 1,000-fold restricted in replication in the respiratory tracts of nonhuman primates compared to human PIV3 (HPIV3), an important pathogen of infants and young children. BPIV3 is also restricted in replication in human infants and children, yet it is immunogenic and is currently being evaluated in clinical trials as a vaccine candidate to protect against illness caused by HPIV3. We have examined the genetic basis for the host range attenuation phenotype of BPIV3 by exchanging each open reading frame (ORF) of a recombinant wild-type HPIV3 with the analogous ORF from BPIV3, with the caveats that the multiple ORFs of the P gene were exchanged as a single unit and that the HN and F genes were exchanged as a single unit. Recombinant chimeric bovine-human PIV3s were recovered from cDNA, and the levels of viral replication in vitro and in the respiratory tract of rhesus monkeys were determined. Recombinant chimeric HPIV3s bearing the BPIV3 N or P ORF were highly attenuated in the upper and lower respiratory tracts of monkeys, whereas those bearing the BPIV3 M or L ORF or the F and HN genes were only moderately attenuated. This indicates that the genetic determinants of the host range restriction of replication of BPIV3 for primates are polygenic, with the major determinants being the N and P ORFs. Monkeys immunized with these bovine-human chimeric viruses, including the more highly attenuated ones, developed higher levels of HPIV3 hemagglutination-inhibiting serum antibodies than did monkeys immunized with BPIV3 and were protected from challenge with wild-type HPIV3. Furthermore, host range determinants could be combined with attenuating point mutations to achieve an increased level of attenuation. Thus, chimeric recombinant bovine-human PIV3 viruses that manifest different levels of attenuation in rhesus monkeys are available for evaluation as vaccine candidates to protect infants from the severe lower respiratory tract disease caused by HPIV3.

Download Full-text

Newcastle Disease Virus V Protein Is a Determinant of Host Range Restriction

Journal of Virology ◽

10.1128/jvi.77.17.9522-9532.2003 ◽

2003 ◽

Vol 77 (17) ◽

pp. 9522-9532 ◽

Cited By ~ 160

Author(s):

Man-Seong Park ◽

Adolfo García-Sastre ◽

Jerome F. Cros ◽

Christopher F. Basler ◽

Peter Palese

Keyword(s):

Newcastle Disease Virus ◽

Host Range ◽

Disease Virus ◽

Newcastle Disease ◽

Range Restriction ◽

V Protein ◽

Species Specific ◽

Chicken Eggs ◽

Host Range Restriction ◽

Embryonated Chicken

ABSTRACT It has been demonstrated that the V protein of Newcastle disease virus (NDV) functions as an alpha/beta interferon (IFN-α/β) antagonist (M. S. Park, M. L. Shaw, J. Muñoz-Jordan, J. F. Cros, T. Nakaya, N. Bouvier, P. Palese, A. García-Sastre, and C. F. Basler, J. Virol. 77:1501-1511, 2003). We now show that the NDV V protein plays an important role in host range restriction. In order to study V functions in vivo, recombinant NDV (rNDV) mutants, defective in the expression of the V protein, were generated. These rNDV mutants grow poorly in both embryonated chicken eggs and chicken embryo fibroblasts (CEFs) compared to the wild-type (wt) rNDV. However, insertion of the NS1 gene of influenza virus A/PR8/34 into the NDV V(−) genome [rNDV V(−)/NS1] restores impaired growth to wt levels in embryonated chicken eggs and CEFs. These data indicate that for viruses infecting avian cells, the NDV V protein and the influenza NS1 protein are functionally interchangeable, even though there are no sequence similarities between the two proteins. Interestingly, in human cells, the titer of wt rNDV is 10 times lower than that of rNDV V(−)/NS1. Correspondingly, the level of IFN secreted by human cells infected with wt rNDV is much higher than that secreted by cells infected with the NS1-expressing rNDV. This suggests that the IFN antagonist activity of the NDV V protein is species specific. Finally, the NDV V protein plays an important role in preventing apoptosis in a species-specific manner. The rNDV defective in V induces apoptotic cell death more rapidly in CEFs than does wt rNDV. Taken together, these data suggest that the host range of NDV is limited by the ability of its V protein to efficiently prevent innate host defenses, such as the IFN response and apoptosis.

Download Full-text