Interruption of cytokine networks by poxviruses: lessons ... - CiteSeerX

Interruption myxoma

of cytokine

networks

by poxviruses:

McFadden,

Martha

Kathryn

Schreiber,

Department

Graham,

Karen

of Biochemistry,

Mossman,

University

Kimberly Piers

of Alberta,

TNF

. serpins

. IFN-y

. virokines

Edmonton,

. viroceptors

INTRODUCTION Many viruses that infect vertebrate hosts achieve sustamed host-to-host transmission by using specific strategies that evade or subvert the consolidated activities of the antiviral immune and inflammatory responses [1-4]. Some of these viral strategies can be revealed by analysis of the interaction between viruses and the many classes of effector cells that directly mediate natural and acquired immunity,

such

as

B

and

T

lymphocytes,

natural

killem

cells, monocytes/macrophages, and antigen-presenting cells [5-8]. For example, many viruses down-regulate cell surface major histocompatibility complex antigens of infected cells as part of a concerted strategy to ciicumvent major histocompatibility complex-restricted recognition of viral antigens [9, 10]. Related strategies have also been uncovered by the identification of viral genes whose protein products are not required for virus replication in tissue host

culture, tissues

but that

are

instead allow for normally visible

virus propagation to the imnmiiune

Ellison, Nash,

Abstract: Myxoma virus is an infectious poxvirus pathogen that induces a virulent systemic disease called myxomatosis in European rabbits. The disease is rapidly and uniformly fatal to susceptible rabbits and is characterized by generalized dysfunction of cellular immunity and multiple interruptions of the host cytokine network. A number ofvirus genes are classified as virulence factors because virus constructs bearing targeted gene disruptions induce attenuated disease symptoms. Many of these genes encode proteins that interact directly with effector elements of the host immune system. Included among these immunosubversive viral proteins are secreted mimics of host ligands or regulators (virokines) and homologues of cellular cytokine receptors (viroceptors). Five examples of these immune modulator proteins encoded by myxoma virus are reviewed: ( 1) myxoma growth factor, a member of the epidermal growth factor ligand superfamily; (2) SERF-i, a secreted serine proteinase inhibitor; (3) Ml 1L, a receptor-like surface protein; (4) T2, a tumor necrosis factor receptor homologue; and (5) T7, an interferon-yreceptor homologue. The origin ofviral strategies designed to subvert immune regulation by host cytokines is considered in the context of the biology of myxoma virus within immunocompetent hosts.J. Leukoc. Biol. 57: 731-738; 1995. Words:

from

virus

Grant

Key

lessons

in amid

inflammatory systems of the host. The larger DNA viruses are of particular interest because they encode more proteins than are necessamy for the assembly of progeny virions [1, 4]. Poxviruses provide an excellent example of

Alshad Alberta,

this,

Barry, Joanne

Michele Lalani,

and

Helen

Macen, Everett

Canada

because

viruses rnously Many factors,

pacity thereby

they are among the largest eukaryotic DNA have the unusual capacity to mcplicate autonowithin the cytoplasm of infected cells [11-13]. poxvirus proteins have been defined as virulence and

because

they

to propagate contribute

disruption

of

confer

within to viral

virulence

the

virus

with

immunocompetent pathogenesis. genes

increased

The

frequently

ca-

hosts deletion

results

and or in

the

attenuation of the pathogenic profile in ‘iso, as determined by reduced levels of poxvirus replication and hosthost transmission [14-16]. In this review we consider how one poxvirus pathogen of rabbits, myxoma virus, interacts with the host immune system and specifically the cytokine network.

Myxoma

virus

Myxoma

rabbit

virus

and myxomatosis first discovered in Uruguay at the

was

pathogen

tury, when imported Ins) were suddenly

European

as a novel end of the

rabbits

(Oryclolagus

infectious 19th cencunicu-

stricken with a previously undescribed disease, later called myxomiiatosis [17, 18]. This disease was found to be transmitted by arthropod vectors, particularly mosquitoes, and ss’as virtually 100% lethal to infected European rabbits. The myxomatosis disease syndrome was characterized by extensive fulminating lesions, both internal and extermial, amid severe immunodysfunction accompanied by supervening Gram-negative bacterial infections of the respiratory tract [17, 19, 20]. The infectious viral agent, myxoma virus, was later shown to be a member of the poxvirus family and to have arisen from populations of the North ahd South American rabbit (Sylvilagus sp.), a distinct genus from that of its European counterpart [17, 18, 21, 22]. Interestingly, in the indigenous rabbits, i.e., Sylvilagus bachinani and Sylvilagus brasiliensis, myxoma virus established a symbiotic yet nonpathogenic relationship, causimig only a persistent infection s’ith minimal cellular immune recognition and only miiinor symptoms [17, 21, 22]. Thus, it is only after infection of the related but distinct European rabbit that the pathogenic syndrome that characterizes full-blown

Abbreviations: EGF, epidernuil growth factor; TN F, tumlior necrosis factor; TUE. transforming growth factor; SF’s’, shope ht)roma virus; MRV, malignamit ral)bit fibroma virus; NICE, iiwxomna gioss-th factor; SFGF, SF’V growth factor; I FN, interferon. Reprint requests: Grant McFadden, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada TOG 2H7 Received November 1, 1994; accepted januai-y 12, 1995.

Journal

of Leukocyte

Biology

Volume

57,

May

1995

731

TABLE

1.

Virokines

and

Viroceptors

Encoded

Cellular

Gene NICF

Virokines

Copy I

No.a

Nlyxonia

by

Virus

Viral protein localization

homologue EGF/TGF-ct

Function Ligand of EGF

Cellular/secreted

Myxomatosis virulence geneb Yes

receptor

(stimulates

SERP-l

2

Serpin

(SPI-4)

Viroceptors

mitogenesis) Inactivates multiple host serine proteinases (inhibits inflammatory response)

Secreted

superfamily

T2 T7 Unmappeif’

2 2 ?

TNF

receptor receptor Interleukin-l

NI IlL

1

?

IFN-y

receptor

Secreted Secreted

Binds Binds

and and

inhibits inhibits

Secreted

Binds

interleukin-Il

Cell sLirface

Inhibits

genes

iv irulence of the

tions

that map within genes are defined

gene

in question

:jsPI_4 is an alternative The

the viral terminal bs’ the attenuation (Nt, not determined).

presumptive

nomenclature equivalent gene

suggested from vaccinia

inverted of the

repeat disease

sequences syndrome

for SERP-l [471. (BI5R) encodes

are present of myxomatosis

a soluble

homologue

myxomatosis manifests itself. The extreme virulence of myxoma virus was exploited in the early 1950’s when the first attempt at irradication of a vertebrate pest with an infectious agent was initiated in Southern Australia. Myxoma virus was imported to Australia

from

South

America

and

was

released

as two copies. caused by infection

into

populations of feral European rabbits that had overrun large areas of the Australian countryside [17]. Although massive reductions in rabbit populations were initially registered, resistant rabbits soon repopulated the infected areas and the dominant field viruses became progressively attenuated [17, 18]. Today, myxoma-resistant rabbit populations in Australia approach the levels found before the original virus releases [23]. Recent studies have focused on the molecular mechanisms by which myxoma virus is able to exert such profound pathological effects on the immune system of European rabbits. Some of the virulence genes encoded by the myxoma virus have been identified and several of the expressed viral proteins have been shown to interact with known components of the host’s immune system [ 24]. Here we review those secreted and cell surface proteins encoded by myxoma virus that modulate host cytokme networks.

of the

cellular

type

with

TNF-a/3 INF-’y

ND Yes

mechanism

recombinant

II interlctikin-I

Yes ND

by

inflammation

unknown

virus

Yes

myxoma

receptor

virus

[86,

svith

targeted

87J.

swinepox virus [32], but the ongoing sequencing studies of other poxvirus genomes may yet reveal other members of this class of membrane-bound viroceptor. The use of virokines and viroceptors to modulate immune recognition has now been described for a variety ol the larger DNA viruses, particularly the poxviruses, indoviruses, and herpesviruses [33, 34]. The specific examples considered here that are encoded by myxoma virus are summarized in Table 1 and illustrate the diversity with which one individual virus can utilize a spectrum ol these defense mechanisms to subvert immune recognition and clearance of the infecting virus.

Myxoma

growth

Currently, cytokine

there homologue

factor is

no example but there

ccc

MGF

N

of a poxvirus-encoded are several examples cc

C

1

37

45 Rec.ptor

51

5bJ Binding

lb

Domain

, HOMOLOG

_‘s,

TO MGF 10000

mgi

and viroceptors

ol

IsAWAJ

POXVIRAI

Virokines

inactiva-

85.00 1191

Virus-encoded proteins that affect the activities of the host immune system can function either intracellularly or extracellularly. The term virokine, initially coined in 1988 to describe a novel virus-encoded epidermal growth factor (EGF)-like growth factor and the 35-kDa secreted complement control protein of vaccinia [25], refers to viral proteins that mimic host ligands (e.g., cytokines or growth factors) or related soluble immune regulators (e.g., complement binding proteins). Later, the term viroceptor was proposed [26] to describe a class of viral proteins that are functional homologues of cellular receptors and act by sequestering host ligands away from their target cellular receptors. Although the first example of a viroceptor was the secreted tumor necrosis factor (TNF) receptor homologue encoded by several poxviruses [ 26-28], it is now apparent that some virus-encoded receptor homologues are not secreted but function at the surface of infected cells. For example, several human and primate herpesviruses encode homologues of cellular chemokine receptors, also called serpentines, that are expressed

exclusively

Currently, serpentine

732

Journal

the only receptor

at the

surface

ofinfected

cells

[29-31].

known example of a poxvirus-encoded homologue has been described in the

of Leukocyte

Biology

Volume

57, May 1995

41.46

vgt

38.89

MAMMALIAN

h-btc

(69)

h-tgfa

(47)

ti-Idgfl

Fig. growth

(75)

1. Comparison factors.

cysteine-rich

The

receptor

of MGF with NIGF putative binding

other members signal sequence

domain

is shown

of

the and

aligned

(104)

44.44

‘8”

44.44

(174)

47.22

(210)

42.50

(106)

56.25

EGF family the conserse

to

other

o

poxviral

and mammalian black boxes and

EGF honiologues. The conserved cysteines are shown a other conserved residues are indicated in white boxes The percentage of homology within the cysteine-nich comisers’ed domain of a number of EGF family members are indicated: sfgf, Shope fibrom2 growth factor; vgf, vaccinia growth factor; vagf, variola growth factor m-egf,

munine

epidermal

human transforming rived growth factor; teratocarcinoma-derived

sequences

are

growth

growth

listed

factor;

h-btc,

growth factor a; m-sdgf, r-ndf, rat neu differentiation elsewhere

factor.

[35].

The

human

accession

h-tgfa

betacellulin;

munine factor;

schwannoma-de. h-tdgfl, htmma numbers

for

thes

growth factor mimicry. The discovery and charactenization of poxvirus-encoded members of the EGF/transforming growth factor-a (TGF-a) superfamily is reviewed elsewhere [14, 15, 35]. As illustrated in Figure 1, all the poxvirus members of this family maintain the six cysteine residues critical for correct folding of the recepton binding domain and all are secreted ligands for the cellular EGF receptor. In myxoma virus and other closely related members of the leporipoxvirus genus, particularly Shope fibroma virus (SFV) and malignant rabbit fibroma virus (MRV), these viral growth factors are encoded by single-copy genes located close to the terminal inverted repeat sequences in the genome [36-38]. The myxoma growth

factor

(MGF)

was

shown

to

be

a bona

fide

mimic

of EGF and TGF-cx in a variety of biological assays that measured signaling events triggered by ligand binding to the EGF receptor [39-42]. To assess the biological consequences of deleting the MGF gene from myxoma virus, and the related SFV growth factor (SFGF) gene in MRV, Opgenorth et al. [43, 44] created recombinant viruses in which the growth factor genes from myxoma and MRV were disrupted by insertion of a selectable marker. The resulting recombinant viruses were virtually normal for replication in a variety of cultured cells but could only induce an attenuated form of myxomatosis in susceptible European rabbits [43, 44]. In particular, rabbits infected with the MGF-disrupted myxoma virus exhibited decreased levels of epithelial hyperplasia and metaplasia, which normally overlay viral lesions of the conjunctiva and respiratory tracts [44]. When similar MGF-disrupted myxoma constructs were engineered to overexpress other EGF-like growth factors, such as rat TGF-ct, the resulting viruses

regained

fected rabbits MGF was indeed therefore likely

wild-type

[45].

levels

These

biologically

to

function

of

results

pathogenicity

clearly

equivalent

by

to

stimulating

in

indicate TGF-ct

host

in-

that and

EGF

is

re-

encode proteins belonging to the superfamily of serine proteinase inhibitors (serpins) [14, 15, 47]. Members of the orthopoxviruses, such as vaccinia, cowpox, rabbitpox, and vaniola, each encode three known serpins that have been designated SPI-1, -2, and -3 [48-58]. Of particular note is SPI-2, also designated crmA in cowpox, which inhibits intenleukin-1-converting enzyme [59], and thus regulates the infiltration of responsive leukocytes [15, 55-58]. Although homologues of SPI-1, -2, or -3 have not been detected in myxoma virus, a related serpin, designated SERP-1, has been described [60]. A schematic representation of the SERP-1 protein and its relationship to other viral and mammalian serpins is given in Figure 2. All active serpins function as pseudosubstrates for the target senine proteinases and form stable 1 : 1 complexes that effectively remove the proteinase from the pool of active enzyme [47, 61]. Among the critical regions for serpin function is the PI-Pi’ site that forms the cleavable peptide bond destined for hydrolysis by the reactive senme in the protease, and this peptide pair in part determines

the

specificity

of

protease(s)

that

can

be

inhibited,

The Pi-PI’ residues ofSERP-1 are Arg-Asn, a unique pair not found in any other serpin, and thus makes prediction of potentially inhibitable serine proteinases difficult [60]. It has been shown that SERP-1 protein will form 1:1 inhibitory

complexes

with

a variety

of

human

serine

prote-

inases, including plasmin, urokinase, tissue plasminogen activator, and at least one of the components of the complement cascade [62]. However, it is still unclear ifany of these proteinases are actually targeted for inhibition by SERP-1 in virus-infected tissues, and it is possible that other potential target proteinases remain to be uncovered. SERP-1 is expressed from a late viral promoter and, unlike any other poxvinal serpin, is secreted from virus-infected cells as a 50- to 55-kDa glycoprotein [63]. Importantly, virus constructs in which both copies of the

ceptors.

A number of models have been suggested to explain how poxvimus growth factors such as MGF might provide a selective advantage for virus propagation in the tissues of a vertebrate host [15, 35]. For example, mitogenic stimulation of quiescent cells in the vicinity of the virus infection would dramatically up-regulate elements of the cellular macromolecular synthesis machinery and thus miprove subsequent virus replication and increase virus titens. By mimicking a ligand for the ubiquitously expressed EGF receptor, vinal gene products like MGF would therefore assist in virus spread within quiescent cells that normally possess depressed pools of nucleotides and other precursors required for efficient viral replication and morphogenesis.

Circumstantial

evidence

predicts

the

presence

of

other

growth factor homologues within the myxoma genome. One of the characteristic histological features of myxomatosis is the dysnegulated proliferation of endothelial cells in the capillamy networks near myxoma viius lesions [20]. Recently, a poxviral homologue of vascular endothelial growth factor has been described for poxvirus of sheep [46] and it is entirely conceivable that myxoma virus might encode a related growth factor. Because the DNAsequencing studies of myxoma virus are not complete, more examples of ligand mimicry may yet be uncovered.

SERP-1: a secreted serine inhibits cellular inflammation Currently, have been

seven distinct discovered

proteinase

inhibitor

serine pnoteinase in poxvirus genomes

that

inhibitor genes all of which

FIFACT

Yr

I-

NH2-jj

c

()

P2-P1iP1’-P2’-P3’-PA’-P5)

PCYYIRA

%5t,isiy,

SrRPiss.

SERP-1 vv

sP:-3

vs

sP:-2

vv spy

s:-i

(MIX

SPI-4)

cmA

D

ll

M

T V

V

S

V

LJ D

SPH7

T

PN

MAMA1ASSrrr’s:

[

R N

I K

A

K

LiLl

hPA hGDN rAIAF

Cons#{149}nsus

A

M

J

L

[iJ

o

S

R

S

S

P

t

E

100

%.ciYTI’’

100

528

287

485

267

530 450

280

537 53 7 507

3149 31 0 2714

223

Fig. 2. Comparison

ofmnyxoma SERP-l witis other poxviral and mammalian serpins. The upper illustration summarizes the consensus serpin features, imicluding the distribution ofcommonly conserved a-helix structunes (light grey, putative helices labeled hA to hI). A portion of the reactive center (black) is expanded to show the amnino acid sequence surroumiding the scissile PI-PI’ bond (arrow). A comparison with a selection of other viral and mammalian serpimis indicates that SERP-l has a unique P1’ asparagine residue (italicized). The consemisus serpin reactive center sequence is indicated and residues corresponding to the consensus are boxed. Alignmnent is by consensus homology of the serpin reactive center. Accession numbers used are: SERP-l, myxoma virus serpin (P12393); SPI-3, vaccinia virus ORF K2L(P20532); VVSPI-2, vaccinia virus cnmA/ORF B13R (M24218); VV SPI-l, vaccinia virus ORF B24R (M24217); SPV SPI-7, swine poxvirus ORF KIR(L2193l); hPAI-l, human plasminogen activator inhibitor (P05121); hGDN, human glia-derived nexin (P07093); rAIAF, rabbit al-antitmypsin (P23035).

McFadden

et al.

Interruption

of cytokine

networks

733

domain.

©

M 1 1 L was originally discovered by accident COOH-terminal end of M 1 1 L was truncated during the construction of an MGF deletion virus due to an overlap in coding sequences between these two genes [44]. Subsequent gene disruption analysis of the MilL gene indicated that Ml 1L was itself a significant virulence factor for the induction of the myxomatosis disease syndrome in susceptible rabbits [44]. When recombinant myxoma virus with a disrupted M 1 1 L gene was used to infect European rabbits, the standard disease symptoms were virtually eliminated and instead benign fibroma-like when

21

Cysleine

18 amino acid membrane-spanning

domain

II uar t

E xtrace

Membrane 166

COOH Intracellular

Fig. 3. Predicted orientation of the myxoma NI I 1 L protein at the infected cell surface. The COtl)H-terminal hydrophobic helix domain (amino acids 143-160), indicated by a shaded box, is presumed to span the plasma meiiibnane once. The COOH-termimial six amino acids are believed to be intracellular, ss’hereas the 142 amino acid NH,-tertninal is shown on the exterior stmrface. The predicted extracellimlar domain has six cvsteine residues (C). The amino acid residue numbers are imidicated on the cliagiatn.

been disrupted grow normally an attenuated myxomatosis by virtue of a more effective infiltration of inflammatory leukocytes to the site of the viral infection [63]. Thus, SERP-1 appears to function by inhibiting some aspect of the cellular inflammatory response. It is unknown whether the direct target of SERP-1 function is the cytokme network, but proimiflammatomy cytokines that require extracellular proteolytic activation would be attractive candidates. More recently, the anti-inflammatory properties of SERP-1 have been exploited for a novel experimental in cultumed

SERP-1 cells

therapy in fied SERP-1 ressel wall jury, the plaque was viral immune expressed,

gene have but cause

a rabbit miiodel protein was after balloon

subsequent

development

inhibited

[64].

defense

for

overly

exuberant

and

therapy

of

is the

such

used

as

disease

as

or

evidence

T2: a secreted Many

normal

‘iruses gagement

can

to

intercept was first

re-

associated excessive immune

with ne-

VIROCEPTORS SFV” Vd.IC2

are

expressed

surface

of

host suggested

receptors,

cytokines when

of proteins

infected

cells

MEMBERS

particularly

before receptor data base analysis

OF THE TNF RECEPTOR

C22t.

d mmI t I i 1 mm m I It m i I 1 t IL I [4 mti i I [I I 11 3 -l1r:::::Il:I:TIIIIJI 1 1t I I I EII ti m .im #{149}m m I 1I_::f1IT m m [F1 fi II .{I mm m i i I mTi m rirrri rmU-

I I m I

Ld

a variety

cytokine

mm m I

1

‘1:1-

viroceptor

to encode

homologue

enof

SUPERFAMILY

(TNF-R) ‘D-

that [14-16],

the pathogenic roles of these cell surface proteins have only recently been investigated. One candidate for a cell surface viroceptor encoded by myxoma virus is vI ilL, Sc) namiied because it is the 11th open reading

Thre

sm 11

m

I

I

I I

I

flC

m

I 1

1

1 t

t

IIC

1L1

I

I

: m

ii

i

im

I

: i

i

p75

TNFR

i

i

i

m

I1

iii

i

m

C,.&.R1d

12 -#{149}c::=m::::i::I:::i:::x__i___1

P.tyzoma

known omi the

cellular

POXVIRAL

v.,Cw.l.

are

receptor

be

Vd,.AS3R

Poxviruses

TNF

those with single membrane-spanning domains, have been found to also exist in secreted soluble form produced by either proteolytic cleavage from the cell surface or alternative splicing [66, 67]. These soluble receptors can potentially function as ligand inhibitors by sequestering extracellular bioactive ligands away from the cell surface receptors. The use of a similar strategy by DNA

C..p..C,,,.$

cell surface

of thatinfiltrating cell sun-

sequent studies revealed that an M 1 1 L variant, which was unable to traffick to the surface but instead was retained in the cytoplasm, was also ineffective at preventing cellulan infiltration, suggesting a surface receptor-like function for Ml 1L [65]. Currently, no close homologue of Ml 1L has been described in the literature and therefore the relationship of Ml 1 L to the cytokine network must remain speculative. One possibility is that Ml 1L is a nonsignaling receptor that recognizes an unidentified ligand important for the inflammatory response. Another hypothesis is that expression of M 1 1 L prevents the elabonation of proinflammatory signals from infected cells, possibly by the regulation of the apoptotic response of certain immune cells to the virus infection.

that

SERP-1

sponses.

Ml 1 L: a candidate

massive [44]. It isinfluxes believed

atherosclerotic

first

immunosuppressive

syndromes

inflammation

When purithe arterial vascular in-

into

of

This

proteins

purified,

agents

for atherosclerosis. infused directly angioplasty-induced

lesions leukocytes characterized were observed by

face expression of M 1 1 L by the wild-type virus somehow prevents effective influx of inflammatory cells, panticularly heterophil lymphocytes and macrophages [44]. Sub-

Plasma

niyxoma

the

I

-c:i:::c:EJ=IzD-

4_-’”

p55

Ld..

Cy.wY.RId

R.p...

however,

frame

from

the

left

genomic

terminus

to the left [44]. As shown small viral protein (166 surface

brane

734

of

infected

region

Journal

and

cells

and

a short

of Leukocyte

and

is transcribed

in Figure 3, MilL is a relatively amino acid) expressed on the possesses (6 amino

Biology

a single acid)

Volume

57,

transmemintracellular

May

1995

Fig. 4. Comparison

of myxoma T2 protein with other poxviral members of the TNF receptor superfamily. Characteristic features of the poxvirus TNF receptor homologrmes including NH-terminal leader sequences, four cysteine-nich repeats, and COOH-terminal domains are compared with each other and the two humnan p55 and p7S TNF receptors [78]. Conserved cysteines are aligned ( )‘ whereas (T) designate frameshifts and ( ) a stop codon in the discontimiuous open reading frames that constitute the A5SR and C22L genes of vaccinia (strain Copenhagen).

I

i i

POXVMAL

the

type

mology designated

II TNF to

receptor

a gene from T2 because

SFV

sequence revealed striking ho[27, 28]. This poxvirus gene,

it

is

the

second

open

reading

frame from the viral genomic terminus, had been sequenced in 1987 and shown to be transcribed as a typical poxvirus early gene [68]. It is now appreciated that these cellular and viral proteins are all examples of a growing TNF receptor superfamily of proteins that share charactenistic cysteine-rich repeats in the ligand binding domain [ 69-71]. Myxoma virus has also been found to encode a closely related T2 protein (Fig. 4), and the targeted disruption of both copies of the myxoma T2 gene revealed that the absence of T2 expression caused significant attenuation of myxomatosis in rabbits [26]. This was the first demonstration that a virus-encoded secreted recepton homologue was biologically important for virus propagation

in a vertebrate

host

and

lead

to

the

proposal

of the

generic term viroceptor [26]. Similar TNF receptor homologues have been detected in other poxviruses, notably cowpox and variola [72-75]. However, as indicated in Figure 4, in the Copenhagen and WR strains of vaccinia, the two T2-like genes are fragmented by virtue of internal stop codons and frameshift mutations [26, 76, 77]. The growing poxvirus TNF receptor homologues family is reviewed in greater detail elsewhere [78]. Studies using myxoma T2 secreted from a vaccinia virus engineered to overexpress T2 indicate that the protein binds and inhibits rabbit TNF-a but not mouse or human TNF-a [79]. Myxoma virus is one of the few poxviruses for which an evolutionary history within one vertebrate species is well established [17, 18], and the species specificity of the myxoma T2 protein is probably a direct reflection of its long symbiotic interrelationship with the South American rabbit [79]. It is thus reasonable to predict that other poxviruses with functional viroceptons will also possess ligand species specificities that reflect their evolutionary history.

T7: a secreted

interferon

(IFN)--y

receptor

homologue

Given the well-documented importance of the IFNs (a, 3, and y) in combating viral infections, it is not surprising that many viruses have evolved distinctive anti-IFN strafegies [80, 81]. Currently, the only known examples of a virus strategy to inhibit IFN before ieceptor/ligand interaction are the poxvirus-encoded soluble IFN-y receptor homologues [82]. The first example discovered was the T7 gene of myxoma, thus called because it is the seventh open reading frame from the tel-minus of the viral genome [83]. The 37-kDa T7 protein is the most abundant protein species secreted from myxoma virus-infected cells, and sequencing studies have revealed significant amino acid similarity to the human and mouse IFN-y receptor (a-chain), particularly at the level of cysteimie residues within the ligand binding domain (Fig. 5). Crosslinking experiments and direct inhibition studies revealed that the T7 protein could bind and prevent the induction of the antiviral state by rabbit IFN-y [83], indicating that T7 was indeed another exaniple of a secreted viroceptor. Later highly IFN--y

WNna

studies indicated that, specific for the rabbit from humans or mice

like ligand [84].

the

T2

protein, T7 was and could riot bind to Intelestingly, Scatchamd

analysis indicated that the K(f for soluble T7/rabbit IFN-y was 1.2 nM, very similar to that reported for the soluble versions of the cellular receptor a-chain for its cognate species IFN-y [82, 84]. It is therefore reasonable to predict that the T7 protein functions by binding and sequestering

S wvwccw

ci’

H

CV

cc

c

sc

KIKDRSL

i

E

:Fm S

MYXOMA

I7

H CY

c

wvwccw

cc

c

sc

KIKOR

SI

L

-ll-1II-EEIll-IHI-1ll---II-I---tI-Ellh

cELLuLARFNn$

wvwccw

cP

H

CV

cc

c

sc

= Fig. acid

5. Comparison of poxviral and niammaliami IFN-y receptors. Amino residues conserved between the soluble poxviral IFN-y receptor homologues amid the mammalian ligand binding domain are indicated with boxes. Cysteitie residues critical for proper folding of the ligand binding

domain

tnature

proteins

are

highlighted

are

with

indicated

on

filled

boxes.

The

length

of

the

the

right. Location of the transmemfunctional domain I are imidicated details and accesskn numbers for all

bramie domain (TNI) and cytoplasmic for the cellular receptors. Further peptides are shown by Mossman et al. [82].

extracellular and natural Currently,

T lymphocytes viral lesions. the role of T7 in myxoma-infected rabbits is available but experiments to test the effect of disrupting both copies of the myxoma T7 gene ame in progress. T7 also possesses a significant stretch of COOH-terminal sequences that have no homologous counterpart in the data base, which raises the possibility that the intact T7 protein has other functions in addition to the bimiding and inhibition of IFN-y. In addition to the T2 and T7 viroceptors, a third class of secreted viroceptom’ has been described for vaccinia and (type

IFN-y produced by activated killer cells that infiltrate the no direct biological data on

cowpox,

viruses

with

homology

to

II) receptor [85-87]. Pmcliminaly that cells infected with myxoma virus interleukin-ii binding protein bin

gene

remains

to

Mossnian, N’IcFadden,

be

miiapped

and

the

intenleukin-1

evidence suggests elaborate a similar the myxoma virus

formally

analyzed

(K.

K. GIahani, unpublished

A. Alcami, G. Smith, and G. obser1ations). Given the rapidity with which the first three secmeted viroceptors were discovered in the poxvirus systemli, it seems likely that miiore examples of this stratetrv still memain to he umu-overt’d

CONCLUSIONS geneially

Poxviiuscs

tract) that are of the imniumie viruses

have

replicate

accessible system. evolved

in

tissues

(skin,

respiratomy

to niany of the effector Thus, it is not surprising active

countcrmiieasures

elements that these to

nullify

at

least some nition and extent and

of the effector mechanisms of immune recogcleaiance. What is perhaps surprising is the breadth of the host ininiune repertoire that can actually be targeted fom subvemsion by specific viral gene products. The [angel’ DNA viruses have the luxury of encoding -ii-us

moore

proteins

replication,

and

thami

are

it

believed

is

minimally

required

that

for

poxviruses, somehow

through their evolutiomiamy histomy, have acquiied the codimig capacity fom a variety of genes that may have been oiigimiall deri-ed froni the host [24, 33, 88, 89]. The molecular nature of such acquisition evemits remain speculative. Because poxviruscs replicate exclusively in the cytoplasm of infected cells amid none of the viral genes possess imitrons, omic hypothesis is that cellular

i%IcFadden

et al.

Interruption

of cytokine

networks

735

genes may have been acquired by necombination through cytoplasmic cDNA intermediates. Even if this were a rare event, if the captured gene conferred some protection from the immune response, then the resulting virus would acquire selective advantage within the infected host. In any event, the repertoire of immunosubvensive viral proteins in many ways are elements of a collective strategic defense initiative that allows virus propagation even in the face of mobilized inflammatory and immune responses. The total number of such poxviral anti-immune proteins is unknown but at least one poxvirus, vaccinia,

has

been

shown

to have

at least

55

open

reading

frames that are dispensable for propagation in tissue cultune [90]. In the case of myxoma virus, only five of the several dozen novel proteins secreted from infected cells have been characterized, which further suggest that the study of myxoma anti-immune strategies is still in its early stages. The myxoma virus model for the study of poxvirus pathogenesis is particularly attractive for a variety of reasons. The evolutionary host for myxoma is well established (American rabbit) and the myxomatosis disease caused when the virus infects a related but distinct host (European rabbit) has a well-defined pathology in an animal well suited for biological experimentation [17-22]. Furthermore, as a consequence of an important and fascinating set of field experiments in Australia and Europe, a collection of natural attenuated variants of the virus, as well as resistant strains of host rabbits are now available. These attenuated viruses and resistant rabbit strains will be invaluable for addressing important basic questions concerning the nature of virus virulence in outbred immunocompetent hosts [17, 18]. With the myxoma model one can also begin to investigate the relationship between virus pathogenesis and the nature of the evolutionary pressures that selected for the acquisition of anti-immune genes. Myxoma virus infection of native American rabbits is virtually asymptomatic, suggesting that the end product of virus-host co-evolution is symbiosis, rather than disease. In the course of this mutual accommodation between the virus and host, poxviruses such as myxoma have clearly adapted to the effector mechanisms of the immune system. This accommodation is directly reflected in the nature and scope of the viral genes that collectively render infected sites apparently invisible to effective immune clearance. However, once the virus has crossed into a susceptible but genetically distinct host, such as the European rabbit, this symbiotic balance between virus and host is altered in ways that are still poorly understood. Instead, the extreme virulence of the myxoma virus in the European rabbit is a powerful testament to the effectiveness of the virus strategies to subvert immune recognition and clearance. Instead of mediating virus survival by promoting nonrecognition in American rabbits, the viral proteins become transformed, in effect, into mediators of viral pathogenesis

in a disease

of European

rabbits.

Hence,

deletion

Journal

of Leukocyte

Biology

Volume

57, May 1995

rently

defined

only those virus gene products that powith the host cytokine network have The collection of myxoma proteins curas

viroceptors

or

virokines

continues

to

grow and it is conceivable that some of these will reveal host ligands or regulator proteins that have not been uncovered by classical studies of the immune system. A case in point is Ml IL, which has no counterpart in the current data base, but which has all the characteristics one might predict for a novel cytokine receptor homologue. Deletion analysis of M 1 1L in the myxoma genome reveals that this gene product is critical for inhibiting some aspect of the inflammatory response, but the mechanism of action remains to be deduced. Note that it is only

because

of

the

ability

to

perform

direct

biological

experiments cal importance lished. Thus,

with mutant constructs of virus that the cnitiof M 1 1L for immune inhibition was estabdata base amialysis of viral genes coupled

with

experimentation

in

‘ides

Finally,

cytokine species bihity

vivo

powerful

tools

it is clear

inhibitor specificity that new

in

with that

which some

proteins for cytokine

the

a biological

system

to address but

(e.g., rabbit inhibitors

not

T2 and ligands. are

all

of

T7)

pro-

these

issues.

the

myxoma

exhibit

Given likely to

strict

the possibe uncov-

ered

in the poxvirus system, it is relevant to note that the poxviruses known to be specific for humans are smallpox (vaniola) and Molluscuin contagiosum. Neither of these two viruses are amenable for experimental analysis in animal models and hence acquisition of biological data from related poxviruses such as myxoma assumes greaten relevance. By the same token, the human poxviruses also encode their own unique spectrum of immune defense molecules, and the recent debate on whether to destroy existing specimens of smallpox [91] should include at least some consideration of the uniqueness of smallpox as a potential source of novel human-specific cytokine inhibitons. Lessons from the myxoma virus system strongly only

suggest

two

that

careful

analysis

of

virus/host

interactions,

both source

in vivo and in vitro, will provide an important refor studying not only issues of virus replication strategies, but the innermost workings of the immune system itself.

ACKNOWLEDGMENTS G. McFadden is a Medical Scientist of the Alberta Hentage Foundation for Medical Research (AHFMR). K. Mossman and P. Nash are supported by studentships from the AHFMR and the MRC of Canada. This work was funded by an operating grant from the National Cancen Institute of Canada.

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736

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