Multifaceted Arsenal of Host Defenses: Unveiling the Intricate Mechanisms That Safeguard Organisms from Pathogenic Threats

Multifaceted Arsenal of Host Defenses: Unveiling the Intricate Mechanisms That Safeguard Organisms from Pathogenic Threats

 

INTRODUCTION

Host defenses in opposition to viruses fall into two main classes:

(1) nonspecific, of which crucial are interferons

and pure killer cells and (2) particular, together with each humoral

and cell-mediated immunity. Interferons are an early, first-

line protection, whereas humoral immunity and cell-mediated

immunity are efficient solely later as a result of it takes a number of days

to induce the humoral and cell-mediated arms of the immune

response.

An outline of how viruses evade our host defenses seems

in Chapter 32.

NONSPECIFIC DEFENSES

1. Alpha & Beta Interferons

Alpha and beta interferons are a gaggle of proteins produced

by human cells after viral an infection (or after publicity to different

inducers). They inhibit the expansion of viruses by blocking the

synthesis of viral proteins. They achieve this by two principal mecha-

nisms: One is a ribonuclease that degrades mRNA, and the

different is a protein kinase that inhibits protein synthesis.

Interferons are divided into three sorts primarily based on the cell

of origin, specifically, leukocyte, fibroblast, and lymphocyte. They

are also called alpha, beta, and gamma interferons, respec-

tively. Alpha and beta interferons, collectively generally known as sort

1 interferon, are induced by viruses, whereas gamma (T cell,

immune) interferon, generally known as sort II interferon, is induced by

antigens and is among the effectors of cell-mediated immunity

(see Chapter 58). The next dialogue of alpha and beta

interferons focuses on the induction and motion of their antiviral

impact (Determine 33–1).

Lambda (λ) interferon, generally known as sort III interferon, is energetic

in opposition to intestinal viruses, particularly rotavirus and norovirus. It

reduces the long-term persistence of virus in intestinal mucosal

cells. The function of lambda interferon in human illness is uncer-

tain and won’t be mentioned additional.

Induction of Alpha & Beta Interferons

The robust inducers of those interferons are viruses and double-

stranded RNAs. Induction is just not particular for a specific virus;

many DNA and RNA viruses are competent inducers, though

they differ in effectiveness. The discovering that double-stranded

RNA, however not single-stranded RNA or DNA, is an efficient inducer

has led to the conclusion {that a} double-stranded RNA is syn-

thesized as a part of the replicative cycle of all inducing viruses.

The double-stranded RNA poly (rI-rC) is among the strongest

inducers and was into consideration as an antiviral agent, however

poisonous unwanted effects prevented its scientific use. The weak inducers

of microbiologic curiosity embrace quite a lot of intracellular bac-

teria and protozoa, in addition to sure bacterial substances such

as endotoxin.

This intensive checklist of inducers makes it clear that induction

of those interferons is just not particular. Equally, their inhibitory

motion is just not particular for any explicit virus. Nevertheless, they’re

usually particular in regard to the host species wherein they act

(i.e., interferons produced by human cells are energetic in human

cells however are a lot much less efficient in cells of different species). It’s

clear, subsequently, that different animals can’t be used as a supply

of interferons for human remedy. Fairly, the genes for human

interferons have been cloned, and interferon for medical use is

now produced by genetic engineering strategies.

Motion of Alpha & Beta Interferons

Interferons inhibit the intracellular replication of all kinds

of DNA and RNA viruses however have little impact on the metabo-

lism of regular cells. The selectivity arises from the presence of

double-stranded RNA in virus-infected cells, which isn’t pres-

ent in uninfected cells.

Interferons haven’t any impact on extracellular virus particles.

Interferons act by binding to a receptor on the cell floor that

alerts the cell to synthesize three proteins, thereby inducing

the “antiviral state” (Determine 33–2). These three proteins are

inactive precursor proteins till they’re activated by double-

stranded RNA synthesized throughout viral replication. In consequence,

these proteins are energetic in virus-infected cells however not in unin-

fected cells.

The three mobile proteins are (1) a 2,5-oligo A synthetase

that synthesizes an adenine trinucleotide (2,5-oligo A), (2) a

ribonuclease that’s activated by 2,5-oligo A and degrades viral

and mobile mRNAs, and (3) a protein kinase that phosphory-

lates an initiation issue (eIF-2) for protein synthesis, thereby

inactivating it. The top result’s that each viral and mobile

protein synthesis is inhibited and the contaminated cell dies. No virus

is produced by that cell, and the unfold of the virus is lowered.

As a result of interferons are produced inside a number of hours of the

initiation of viral replication, they act within the early section of viral

ailments to restrict the unfold of virus. In distinction, antibody begins

to seem within the blood a number of days after an infection.

Alpha interferon has been authorised to be used in sufferers with

condyloma acuminatum and power energetic hepatitis brought on by

hepatitis B and C viruses. Beta interferon is used within the treat-

ment of a number of sclerosis. Gamma interferon reduces recurrent

infections in sufferers with power granulomatous illness (see

Chapter 68). Interferons are additionally used clinically in sufferers with

cancers resembling Kaposi’s sarcoma and bushy cell leukemia.

2. Pure Killer Cells

Pure killer (NK) cells are an essential a part of the innate

defenses in opposition to virus-infected cells. They’re known as “pure”

killer cells as a result of they’re energetic with out the need of

being uncovered to the virus beforehand and since they aren’t

particular for any virus. NK cells are a kind of T lymphocyte however

wouldn’t have an antigen receptor. They acknowledge virus-infected

cells by the absence of sophistication I MHC (main histocompatibility

advanced) proteins on the floor of the virus-infected cell. They

kill virus-infected cells by secreting perforins and granzymes,

which trigger apoptosis of the contaminated cells. (See web page 489 for

extra data.)

3. Phagocytosis

Macrophages, notably mounted macrophages of the reticuloen-

dothelial system and alveolar macrophages, are the essential

cell sorts in limiting virus an infection. In distinction, polymor-

phonuclear leukocytes are the predominant mobile protection in

bacterial infections.

4. α-Defensins

α-Defensins are a household of positively charged peptides with

antiviral exercise. (Additionally they have antibacterial exercise; see

Chapter 8.) They intervene with human immunodeficiency

virus (HIV) binding to the CXCR4 receptor and block entry

of the virus into the cell. The manufacturing of α-defensins might

clarify why some HIV-infected people are long-term

“nonprogressors

5. Apolipoprotein B RNA-Enhancing

Enzyme (APOBEC3G)

APOBEC3G is a crucial member of the innate host defenses

in opposition to retroviral an infection, particularly in opposition to HIV. APOBEC3G

is an enzyme that causes hypermutation in retroviral DNA by

deaminating cytosines in each mRNA and retroviral DNA,

thereby inactivating these molecules and lowering infectivity.

HIV defends itself in opposition to this innate host protection by producing

Vif (viral infectivity protein), which counteracts APOBEC3G,

thereby stopping hypermutation from occurring.

6. Fever

Elevated physique temperature might play a job in host defenses,

however its significance is unsure. Fever might act in two methods:

(1) The upper physique temperature might instantly inactivate the

virus particles, notably enveloped viruses, that are extra

heat-sensitive than nonenveloped viruses and (2) replication of

some viruses is lowered at larger temperatures; subsequently, fever

might inhibit replication.

7. Mucociliary Clearance

The mucociliary clearance mechanism of the respiratory tract

might defend the host. Its injury (e.g., from smoking) outcomes

in an elevated frequency of viral respiratory tract infections,

particularly influenza.

8. Circumcision

There’s proof that circumcision prevents an infection by

three sexually transmitted viruses: HIV, human papillomavirus

(HPV), and herpes simplex virus sort 2 (HSV-2).

9. Elements That Modify Host Defenses

A number of elements affect host defenses in a nonspecific or mul-

tifactorial manner:

(1) Age is a major variable within the final result of viral

infections. Normally, infections are extra extreme in neonates

and within the aged than in older youngsters and younger adults. For

instance, influenza is usually extra extreme in older folks than

in youthful adults, and herpes simplex virus infections are extra

extreme in neonates than in adults.

(2) Elevated corticosteroid ranges predispose to extra extreme

infections with some viruses, resembling varicella-zoster virus; the use

of topical cortisone in herpetic keratitis can exacerbate eye dam-

age. It’s not clear how these results are mediated, as a result of cortico-

steroids could cause quite a lot of pertinent results, specifically, lysis of

lymphocytes, decreased recruitment of monocytes, inhibition of

interferon manufacturing, and stabilization of lysosomes.

(3) Malnutrition results in extra extreme viral infections (e.g.,

there’s a a lot larger dying charge from measles in growing

international locations than in developed ones). Poor vitamin causes

decreased immunoglobulin manufacturing and phagocyte exercise

in addition to lowered pores and skin and mucous membrane integrity.

SPECIFIC DEFENSES

There’s proof for pure resistance to some viruses in cer-

tain species, which might be primarily based on the absence of receptors

on the cells of the resistant species. For instance, some folks

are proof against HIV an infection as a result of they lack one of many che-

mokine receptors that mediate entry of the virus into the cell.

Nevertheless, by far, crucial sort of protection is acquired

immunity, both actively acquired by publicity to the virus or

passively acquired by the switch of immune serum. Lively

immunity could be elicited by contracting the precise illness, by

having an inapparent an infection, or by being vaccinated.

1. Lively Immunity

Lively immunity, within the type of each antibodies and cytotoxic

T cells, is essential within the prevention of viral ailments.

The primary publicity to a virus, whether or not it causes an inapparent

an infection or symptomatic illness, stimulates the manufacturing of

antibodies and the activation of cytotoxic T cells. The function that

antibodies and cytotoxic T cells play within the restoration from this

first an infection is unsure and should fluctuate from virus to virus, however

it’s clear that they play a vital function in defending in opposition to dis-

ease when uncovered to the identical virus at a while sooner or later.

The period of safety varies; disseminated viral infec-

tions resembling measles and mumps confer lifelong immunity

in opposition to recurrences, however localized infections such because the com-

mon chilly often impart solely a quick immunity of a number of

months. IgA confers safety in opposition to viruses that enter

by the respiratory and gastrointestinal mucosa, and IgM

and IgG defend in opposition to viruses that enter or are unfold by

the blood. The lifelong safety in opposition to systemic viral infec-

tions such because the childhood ailments measles, mumps, rubella,

and chickenpox (varicella) is a operate of the anamnestic (sec-

ondary) response of IgG. For sure respiratory viruses such

as parainfluenza and respiratory syncytial viruses, the IgA titer

in respiratory secretions correlates with safety, whereas

the IgG titer doesn’t. Sadly, safety by IgA in opposition to

most respiratory tract viruses often lasts lower than 5 years.

The function of energetic immunity in restoration from a viral infec-

tion is unsure. As a result of restoration often precedes the appear-

ance of detectable humoral antibody, immunoglobulins might

not be essential. Additionally, youngsters with agammaglobulinemia

get better from measles infections usually and could be immu-

nized in opposition to measles efficiently, indicating that cell-mediated

immunity performs an essential function. That is supported by the

commentary that youngsters with congenital T-cell deficiency are

susceptible to extreme infections with measles virus and herpes-

viruses. T cells are essential in restoration from many however not all

viral sicknesses.

The safety provided by energetic immunity could be affected

by the phenomenon of authentic antigenic sin. This time period refers

to the commentary that when an individual is uncovered to a virus that

cross-reacts with one other virus to which that particular person was

beforehand uncovered, extra antibody could also be produced in opposition to

the unique virus than in opposition to the present one. It seems that

the immunologic reminiscence cells can reply to the unique

antigenic publicity to a better extent than to the next

one. This was noticed in folks with antibodies to the A1 sort

of influenza virus, who, when uncovered to the A2 sort, produced

massive quantities of antibody to A1 however little or no antibody to the A2

virus. It is usually the underlying reason behind extreme hemorrhagic den-

gue fever (see Chapter 42). This phenomenon has two sensible

penalties as nicely: (1) makes an attempt to vaccinate folks in opposition to

the completely different influenza virus strains could also be much less efficient than

anticipated and (2) epidemiologic research primarily based on measurement

of antibody titers might yield deceptive outcomes.

How does antibody inhibit viruses? There are two principal

mechanisms. The primary is neutralization of the infectivity of the

virus by antibody binding to the proteins on the outer floor

of the virus. This binding has two results: (1) It might probably forestall the

interplay of the virus with cell receptors and (2) it could possibly cross-

hyperlink the viral proteins and stabilize the virus in order that uncoating

doesn’t happen. In consequence, the virus can not replicate.

Moreover, antibody-coated virus is extra quickly phago-

cytized than regular virus, a course of much like the opsonizing

impact of antibody on micro organism. Antibody doesn’t degrade the

virus particle; totally infectious virus could be recovered by dis-

sociating the virus–antibody advanced. Incomplete, additionally known as

“blocking,” antibody can intervene with neutralization and type

immune complexes, that are essential within the pathogenesis

of sure ailments. Some viruses, resembling herpesviruses, can

unfold from cell to cell throughout intercellular bridges, eluding the

neutralizing impact of antibody.

Antibodies that intervene with the adherence (adsorption and

penetration) of viruses to cell surfaces are known as neutralizing

antibodies. Notice that neutralizing antibody is directed in opposition to

the floor proteins of the virus, usually the proteins concerned

with the interplay of the virus with receptors on the floor

of the host cell. Antibodies fashioned in opposition to inner parts

of the virus (e.g., the core antigen of hepatitis B virus) don’t

neutralize the infectivity of the virus.

The second principal mechanism is the lysis of virus-infected

cells within the presence of antibody and complement. Antibody

binds to new virus-specific antigens on the cell floor and

then binds complement, which enzymatically degrades the cell

membrane. As a result of the cell is killed earlier than the total yield of virus

is produced, the unfold of virus is considerably lowered.

Lysis of virus-infected cells can be brought on by cytotoxic T

lymphocytes. These CD8-positive T cells acknowledge viral anti-

gen solely when it’s offered in affiliation with class I MHC

proteins (see Chapter 58). They kill virus-infected cells by three

strategies: (1) by releasing perforins, which make holes within the

cell membrane of the contaminated cells; (2) by releasing proteolytic

enzymes known as granzymes into the contaminated cell, which degrade

the cell contents; and (3) by activating the FAS protein, which

causes programmed cell dying (apoptosis).

Not all virus infections induce antibodies. Tolerance to viral

antigens can happen when the virus an infection develops in a fetus

or new child toddler. The mannequin system wherein tolerance has

been demonstrated is lymphocytic choriomeningitis (LCM)

an infection in mice. If LCM virus is inoculated right into a new child

mouse, the virus replicates broadly, however no antibodies are fashioned

throughout the lifetime of the animal. The virus is acknowledged as

“self,” as a result of it was current on the time of maturation of the

immune system. If LCM virus is given to an grownup mouse, anti-

our bodies are fashioned usually. There isn’t a instance of complete toler-

ance to a virus in people; even in congenital rubella syndrome,

wherein the virus infects the fetus, some antibody in opposition to

rubella virus is made. Nevertheless, virus manufacturing and shedding

can go on for months or years.

Suppression of the cell-mediated response can happen throughout

an infection by sure viruses. One of the best-known instance is the loss

of tuberculin pores and skin check reactivity throughout measles an infection. Infec-

tion by cytomegalovirus or HIV may trigger suppression.

Some viruses can “downregulate” (cut back) the quantity of sophistication I

and sophistication II MHC protein made by cells, which can be a mecha-

nism by which these viruses suppress cell-mediated immunity.

2. Passive Immunity

Switch of human serum containing the suitable antibodies

supplies immediate short-term immunity for people uncovered

to sure viruses. The time period passive refers back to the administra-

tion of preformed antibodies. Two sorts of immune globulin

preparations are used for this goal. One has a excessive titer

of antibody in opposition to a selected virus, and the opposite is a pooled

pattern from plasma donors that accommodates a heterogeneous

combination of antibodies with decrease titers. The immune globu-

lins are ready by alcohol fractionation, which removes any

viruses within the serum. The three most continuously used high-titer

preparations are used after publicity to hepatitis B, rabies, and

varicella-zoster viruses. Low-titer immune globulin is used

primarily to stop hepatitis A in folks touring to areas the place

this an infection is hyperendemic.

Two specialised examples of passive immunity embrace the

switch of IgG from mom to fetus throughout the placenta and the

switch of IgA from mom to new child in colostrum.

3. Herd Immunity

“Herd immunity” (also called “group immunity”) is

the safety of a person from an infection by advantage of the

different members of the inhabitants (the herd) being incapable of

transmitting the virus to that particular person (Determine 33–3). Herd

immunity could be achieved by immunizing a inhabitants with a

vaccine that interrupts transmission, such because the dwell, attenuated

FIGURE 33–3 Herd immunity. Immunization of the 9 folks

(tan colour) can defend the one unimmunized particular person (purple colour) by

interrupting transmission. Immunization ranges of 90% are typically

considered enough to guard the unimmunized particular person.

polio vaccine, however not with a vaccine that doesn’t interrupt

transmission, such because the killed polio vaccine (regardless that it

protects the immunized particular person in opposition to illness). Notice that

herd immunity happens with the dwell polio vaccine primarily

as a result of it induces secretory IgA within the intestine, which inhibits

an infection by virulent virus, thereby stopping its transmission

to others. As well as, the dwell virus within the vaccine can replicate

within the immunized particular person and unfold to different members of the

inhabitants, thereby growing the variety of folks protected.

Nevertheless, the essential function so far as herd immunity is con-

cerned is the induction of IgA, which prevents transmission.

Herd immunity could be achieved by pure an infection as nicely

as vaccines. For instance, if a viral illness, resembling measles,

occurred in roughly 90% of a gaggle, and if those that

recovered from the illness had enough immunity to stop

them from changing into contaminated and serving as a supply of virus

for others, then the remaining 10% of the group are protected

by herd immunity.