MM: I would like to see much more in the Special Issue: Microbial seroprevalent in the general population

way of ‘Citizen Science’ in microbiology. Endurance [3]. HAdV infections range in severity from
Many researchers are exploring exactly asymptomatic to life-threatening, with
that, and they need showcasing. I also think
that every microbiology course needs a Spotlight immunocompromised individuals at
greatest risk. HAdV replication is typically
small independent project for students.
These small-scale projects really lead to
The Persistent described as rapid and cytolytic, based on
cell culture models using highly permissive
ownership and improved outcomes. Mystery of transformed human tumor cells. However,
Microbiology is not a stack of notecards; acute lytic replication based on tumor cell
it's a process and a way of thinking. I try to Adenovirus models is only part of the life story of
teach this kind of ‘microbiocentricity’ (or
even ‘microbial supremacy’) in the class-
Persistence HAdV, and recent studies have begun
to reveal important differences in the con-
room, or when I speak to the public. My Cason R. King,1 Ali Zhang,1 text of more normal cells [4–6]. This is
goal remains to change the way people and Joe S. Mymryk1,2,3,* highly relevant to human disease, as it is
think about what I call ‘matters microbial’. also well known that persistent shedding
I also remind listeners of the lesson that the of HAdV occurs from infected individuals
tattoo on my right arm states: Avete Parvuli Human adenovirus (HAdV) often causes long after the primary infection appears to
Domini. All Hail the Small Masters. acute, lytic infections which are readily have resolved [1,2,6,7].
recapitulated in culture models. Alterna-
VT: We desperately need to find a way to tively, HAdV can establish persistent infec- A long-awaited breakthrough in HAdV
make microbiology ‘cool’ again. While tions which have been difficult to biology was recently reported by Zheng
tragedies like the recent Ebola crisis, reproduce in cell culture and are poorly et al., who described a mechanism
now the Zika virus, and the seriousness understood. A recent study reveals how explaining how HAdV can induce a per-
of multidrug-resistant bacteria and the HAdV can re-task the host cell antiviral sistent infection in normal, nontrans-
recent outbreaks of foodborne illnesses response to establish persistence. formed human cells [6]. This is the first
have put microbes on the map and in report of a model of HAdV persistence
the news, we also need to do a better Persistent infection by HAdV and the con- in cell culture, and this allowed the authors
job highlighting and explaining to lay peo- text in which it occurs has been a poorly to address questions related to viral per-
ple the broader outcomes of microbiolog- understood puzzle since the original isola- sistence that have persistently plagued
ical research –CRISPR/Cas9 and its tion of this virus in 1953 from tonsils and adenovirologists. The foundation of this
application in genome editing comes to adenoids of healthy individuals [1]. In con- work was based on the well-established
mind. This is a job not only for scientists, trast to acute or lytic viral infections, per- observation that HAdV replication in can-
but also for publishers, magazines, and sistent infections are characterized as cer cell lines was fully resistant to treat-
news outlets. Lastly, the recent unpleas- long-term with occasional and low-level ment by interferons (IFNs), which are key
ant encounters with highly virulent and, in shedding of progeny virus that may cause antiviral cytokines [8]. However, recent
some cases, lethal microbes also highlight little or no harm to host tissue [2]. Persis- reports suggesting that HAdV reacts to
something very important – we need to tence is an effective and common strategy IFN differently in the context of nontrans-
commit sustainable additional resources for maintaining virus production beyond formed cells [4,5] inspired Zheng et al. to
to battle these pathogens. the primary infection, while simultaneously reopen these investigations [6]. In con-
avoiding immune surveillance. The mech- trast to IFN-responsive A549 lung adeno-
1
Department of Microbiology, Radboud University, anisms dictating whether a viral insult carcinoma cells, treatment of primary
Nijmegen, The Netherlands results in an acute or persistent infection normal human bronchial epithelial cells
or nontransformed diploid fibroblasts with
2
Department of Biology, University of Puget Sound,
have critical implications with respect to
Tacoma, WA 98416, USA
3
Department of Microbiology, Tumor and Cell Biology disease pathogenesis, fueling an ever- either type I or II IFN greatly curtailed
(MTC), Karolinska Institutet, Stockholm, Sweden active quest to understand this aspect infection. This important result demon-
4
Department of Microbiology, New York University School
of virus–host interaction. strates that HAdV is not fully resistant to
of Medicine, New York, NY 10016, USA
IFN, as previously thought, and further-
*Correspondence: m.jetten@science.ru.nl HAdVs are small, nonenveloped DNA more indicates that some aspects of IFN
(M.S.M. Jetten), momartin@pugetsound.edu
viruses that infect a variety of tissues, response are compromised in the tumor
(M.O. Martin), Ute.Romling@ki.se (U. Römling),
Victor.Torres@nyumc.org (V.J. Torres). including the respiratory tract, gastrointes- cell models commonly used for these
http://dx.doi.org/10.1016/j.tim.2016.02.020 tinal tract, and eye, and are highly types of studies.

Trends in Microbiology, May 2016, Vol. 24, No. 5 323

Pursuing these findings, the authors
describe an elegant molecular mechanism
by which HAdV hijacks IFN signalling to
hyperphosphorylated form to the active,
growth-suppressing hypophosphorylated
form by downregulating cyclin-dependent
1
Department of Microbiology & Immunology, University of
Western Ontario, London, Ontario, Canada
2
Departments of Oncology and Otolaryngology, University
of Western Ontario, London, Ontario, Canada

repress transcription of E1A, the first viral

gene expressed during infection. IFNs
dramatically slow the progress of infection
kinase (Cdk) activity [10]. This occurs
through a variety of mechanisms, includ-
ing induction of Cdk inhibitors and/or
3
London Regional Cancer Program and Lawson Health
Research Institute, London, Ontario, Canada
*Correspondence: jmymryk@uwo.ca (J.S. Mymryk).

by directly repressing expression of the reduced expression or activity of Cdks http://dx.doi.org/10.1016/j.tim.2016.02.007

immediate early E1A gene, whose protein
is essential for activating expression of the
other HAdV early genes and reprogram-
ming the cell into a state conducive to
infection [9]. This establishes conditions
leading to a persistent HAdV infection in
cultures of normal human cells, which
steadily produce intermediate amounts
and their cyclin regulatory units. It will be
interesting to determine how this occurs in
HAdV persistence, particularly as Zheng
et al. [6] report that type I and type II IFNs
lead to occupancy of the repressive ele-
ment by different Rb family members. It
also remains to be determined exactly
which defects exist in this pathway in
References
1. Rowe, W.P. et al. (1953) Isolation of a cytopathogenic
agent from human adenoids undergoing spontaneous
degeneration in tissue culture. Proc. Soc. Exp. Biol.
Med. 84, 570–573
2. Zhang, Y. et al. (2010) Modeling adenovirus latency in
human lymphocyte cell lines. J. Virol. 84, 8799–8810
3. Lion, T. (2014) Adenovirus infections in immunocompetent
and immunocompromised patients. Clin. Microbiol. Rev.
27, 441–462

of infectious virus over a time frame
exceeding 100 days, with limited cyto-
pathic effect [6].
Extensive mutagenesis identified a cis-
acting repressive element within the E1A
enhancer necessary for establishing per-
sistence in response to IFN. Using chro-
matin immunoprecipitation, IFN treatment
was shown to cause recruitment of
repressor complexes comprising the Rb
family of tumor suppressors and associ-
ated E2F transcription factors to this site.
This occupancy was also correlated to a
reduction in binding by the GABP tran-
scription factors at an adjacent regulatory
tumor cell models, such as the IFN- 4. Chahal, J.S. et al. (2012) The human adenovirus type 5 E1B
55 kDa protein obstructs inhibition of viral replication by
responsive A549 adenocarcinoma cells type I interferon in normal human cells. PLoS Pathog. 8,
typically used in HAdV studies. Further- e1002853
5. Toth, K. et al. (2015) STAT2 knockout Syrian hamsters
more, the ability of E1A to overcome the support enhanced replication and pathogenicity of
challenges presented in a growth-arrested human adenovirus, revealing an important role of type I
interferon response in viral control. PLoS Pathog. 11,
cell in contrast to an IFN-treated cell could e1005084
provide the key to understanding the role 6. Zheng, Y. et al. (2016) E2F/Rb family proteins mediate
of E2F in both lytic and persistent interferon induced repression of adenovirus immediate
early transcription to promote persistent viral infection.
infections. PLoS Pathog. 12, e1005415
7. Garnett, C.T. et al. (2009) Latent species C adenoviruses in
human tonsil tissues. J. Virol. 83, 2417–2428
Overall, these findings identify a remark-
8. Hendrickx, R. et al. (2014) Innate immunity to adenovirus.
able mechanism by which a virus re-tasks Hum. Gene Ther. 25, 265–284
an antiviral cytokine response to establish 9. Pelka, P. et al. (2008) Intrinsic structural disorder in adeno-
virus E1A: a viral molecular hub linking multiple diverse
a persistent infection. Persistence likely processes. J. Virol. 82, 7252–7263
benefits the virus by allowing the continu- 10. Sangfelt, O. et al. (2000) Mechanisms of interferon-induced
ous production of new progeny at inter- cell cycle arrest. Front. Biosci. 5, D479–D487

site, which normally induce high levels of
E1A expression immediately upon infec-
tion. As expected, viruses lacking this
repressive element fail to establish a per-
sistent state in response to IFN treatment.
Fascinatingly, this genetic element and
functional repression by IFN treatment
are conserved between distantly related
HAdV species, suggesting that this regu-
lation serves an important evolutionary
function.
Despite a clear role for Rb and family
members in IFN mediated repression of
E1A expression, the linkage between
these two pathways in the establishment
of HAdV persistence has not yet been
investigated. It is well established that
IFN treatment can shift the phosphoryla-
tion state of Rb from the inactive
mediate levels over a vastly extended
timeframe. Consequently, the total num-
ber of viral progeny produced by persis- Special Issue: Microbial
tent infections may exceed the number Endurance
produced by acute and self-limiting infec-
tions. Furthermore, the substantially
reduced level of viral protein produced dur-
Spotlight
ing a persistent infection will limit viral anti- Quantifying Current
gen presentation, potentially avoiding
detection and destruction of the infected Events Identifies a
cell by the immune system. The establish- Novel Endurance
ment of this first in vitro model of persistent
HAdV infection brings a new level of com- Regulator
plexity and understanding to the replicative 1,2
cycle of this highly prevalent human patho- Theresa C. Henry and
1,3,
gen. Besides providing the opportunity to Mark P. Brynildsen *
further dissect the molecular mechanism
involved in establishing persistence, these In nongrowing microbes, proteome
studies may also lead to the development turnover is reduced and identifica-
of drugs to facilitate rapid viral clearance. tion of newly synthesized,

324 Trends in Microbiology, May 2016, Vol. 24, No. 5